G2Cdb::Gene report

Gene id
G00000758
Gene symbol
Dync1h1 (MGI)
Species
Mus musculus
Description
dynein cytoplasmic 1 heavy chain 1
Orthologue
G00002007 (Homo sapiens)

Databases (8)

Gene
ENSMUSG00000018707 (Ensembl mouse gene)
13424 (Entrez Gene)
1178 (G2Cdb plasticity & disease)
Gene Expression
NM_030238 (Allen Brain Atlas)
13424 (Genepaint)
Literature
600112 (OMIM)
Marker Symbol
MGI:103147 (MGI)
Protein Sequence
Q9JHU4 (UniProt)

Synonyms (6)

  • Dnchc1
  • Dnec1
  • Loa
  • MAP1C
  • Swl
  • dynein heavy chain, retrograde transport

Literature (55)

Pubmed - other

  • Stable kinesin and dynein assemblies drive the axonal transport of mammalian prion protein vesicles.

    Encalada SE, Szpankowski L, Xia CH and Goldstein LS

    Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, 92093, USA. sencalada@ucsd.edu

    Kinesin and dynein are opposite-polarity microtubule motors that drive the tightly regulated transport of a variety of cargoes. Both motors can bind to cargo, but their overall composition on axonal vesicles and whether this composition directly modulates transport activity are unknown. Here we characterize the intracellular transport and steady-state motor subunit composition of mammalian prion protein (PrP(C)) vesicles. We identify Kinesin-1 and cytoplasmic dynein as major PrP(C) vesicle motor complexes and show that their activities are tightly coupled. Regulation of normal retrograde transport by Kinesin-1 is independent of dynein-vesicle attachment and requires the vesicle association of a complete Kinesin-1 heavy and light chain holoenzyme. Furthermore, motor subunits remain stably associated with stationary as well as with moving vesicles. Our data suggest a coordination model wherein PrP(C) vesicles maintain a stable population of associated motors whose activity is modulated by regulatory factors instead of by structural changes to motor-cargo associations.

    Funded by: NIA NIH HHS: AG000216, AG032180, R01 AG032180, R01 AG032180-01, R01 AG032180-02, R01 AG032180-03, R01 AG032180-04, R01 AG032180-05, T32 AG000216; NIGMS NIH HHS: T32 GM008806; NINDS NIH HHS: P30 NS047101

    Cell 2011;144;4;551-65

  • Neuromuscular junction defects in mice with mutation of dynein heavy chain 1.

    Courchesne SL, Pazyra-Murphy MF, Lee DJ and Segal RA

    Department of Cancer Biology, Dana Farber Cancer Institute, Boston, Massachusetts, United States of America.

    Disruptions in axonal transport have been implicated in a wide range of neurodegenerative diseases. Cramping 1 (Cra1/+) and Legs at odd angles (Loa/+) mice, with hypomorphic mutations in the dynein heavy chain 1 gene, which encodes the ATPase of the retrograde motor protein dynein, were originally reported to exhibit late onset motor neuron disease. Subsequent, conflicting reports suggested that sensory neuron disease without motor neuron loss underlies the phenotypes of Cra1/+ and Loa/+ mice. Here, we present behavioral and anatomical analyses of Cra1/+ mice. We demonstrate that Cra1/+ mice exhibit early onset, stable behavioral deficits, including abnormal hindlimb posturing and decreased grip strength. These deficits do not progress through 24 months of age. No significant loss of primary motor neurons or dorsal root ganglia sensory neurons was observed at ages where the mice exhibited clear symptomatology. Instead, there is a decrease in complexity of neuromuscular junctions. These results indicate that disruption of dynein function in Cra1/+ mice results in abnormal morphology of neuromuscular junctions. The time course of behavioral deficits, as well as the nature of the morphological defects in neuromuscular junctions, suggests that disruption of dynein function in Cra1/+ mice causes a developmental defect in synapse assembly or stabilization.

    Funded by: NINDS NIH HHS: R01 NS050674

    PloS one 2011;6;2;e16753

  • A high-resolution anatomical atlas of the transcriptome in the mouse embryo.

    Diez-Roux G, Banfi S, Sultan M, Geffers L, Anand S, Rozado D, Magen A, Canidio E, Pagani M, Peluso I, Lin-Marq N, Koch M, Bilio M, Cantiello I, Verde R, De Masi C, Bianchi SA, Cicchini J, Perroud E, Mehmeti S, Dagand E, Schrinner S, Nürnberger A, Schmidt K, Metz K, Zwingmann C, Brieske N, Springer C, Hernandez AM, Herzog S, Grabbe F, Sieverding C, Fischer B, Schrader K, Brockmeyer M, Dettmer S, Helbig C, Alunni V, Battaini MA, Mura C, Henrichsen CN, Garcia-Lopez R, Echevarria D, Puelles E, Garcia-Calero E, Kruse S, Uhr M, Kauck C, Feng G, Milyaev N, Ong CK, Kumar L, Lam M, Semple CA, Gyenesei A, Mundlos S, Radelof U, Lehrach H, Sarmientos P, Reymond A, Davidson DR, Dollé P, Antonarakis SE, Yaspo ML, Martinez S, Baldock RA, Eichele G and Ballabio A

    Telethon Institute of Genetics and Medicine, Naples, Italy.

    Ascertaining when and where genes are expressed is of crucial importance to understanding or predicting the physiological role of genes and proteins and how they interact to form the complex networks that underlie organ development and function. It is, therefore, crucial to determine on a genome-wide level, the spatio-temporal gene expression profiles at cellular resolution. This information is provided by colorimetric RNA in situ hybridization that can elucidate expression of genes in their native context and does so at cellular resolution. We generated what is to our knowledge the first genome-wide transcriptome atlas by RNA in situ hybridization of an entire mammalian organism, the developing mouse at embryonic day 14.5. This digital transcriptome atlas, the Eurexpress atlas (http://www.eurexpress.org), consists of a searchable database of annotated images that can be interactively viewed. We generated anatomy-based expression profiles for over 18,000 coding genes and over 400 microRNAs. We identified 1,002 tissue-specific genes that are a source of novel tissue-specific markers for 37 different anatomical structures. The quality and the resolution of the data revealed novel molecular domains for several developing structures, such as the telencephalon, a novel organization for the hypothalamus, and insight on the Wnt network involved in renal epithelial differentiation during kidney development. The digital transcriptome atlas is a powerful resource to determine co-expression of genes, to identify cell populations and lineages, and to identify functional associations between genes relevant to development and disease.

    Funded by: Medical Research Council: MC_U127527203; Telethon: TGM11S03

    PLoS biology 2011;9;1;e1000582

  • Mutations in cytoplasmic dynein lead to a Huntington's disease-like defect in energy metabolism of brown and white adipose tissues.

    Eschbach J, Fergani A, Oudart H, Robin JP, Rene F, Gonzalez de Aguilar JL, Larmet Y, Zoll J, Hafezparast M, Schwalenstocker B, Loeffler JP, Ludolph AC and Dupuis L

    Inserm, U692, Strasbourg, F-67085 France.

    The molecular motor dynein is regulated by the huntingtin protein, and Huntington's disease (HD) mutations of huntingtin disrupt dynein motor activity. Besides abnormalities in the central nervous system, HD animal models develop prominent peripheral pathology, with defective brown tissue thermogenesis and dysfunctional white adipocytes, but whether this peripheral phenotype is recapitulated by dynein dysfunction is unknown. Here, we observed prominently increased adiposity in mice harboring the legs at odd angles (Loa/+) or the Cramping mutations (Cra/+) in the dynein heavy chain gene. In Cra/+ mice, hyperadiposity occurred in the absence of energy imbalance and was the result of impaired norepinephrine-stimulated lipolysis. A similar phenotype was observed in 3T3L1 adipocytes upon chemical inhibition of dynein showing that loss of functional dynein leads to impairment of lipolysis. Ex vivo, dynein mutant adipose tissue displayed increased reactive oxygen species production that was, at least partially, responsible for the decreased cellular responses to norepinephrine and subsequent defect in stimulated lipolysis. Dynein mutation also affected norepinephrine efficacy to elicit a thermogenic response and led to morphological abnormalities in brown adipose tissue and cold intolerance in dynein mutant mice. Interestingly, protein levels of huntingtin were decreased in dynein mutant adipose tissue. Collectively, our results provide genetic evidence that dynein plays a key role in lipid metabolism and thermogenesis through a modulation of oxidative stress elicited by norepinephrine. This peripheral phenotype of dynein mutant mice is similar to that observed in various animal models of HD, lending further support for a functional link between huntingtin and dynein.

    Funded by: Medical Research Council: G0300854

    Biochimica et biophysica acta 2011;1812;1;59-69

  • A cytoplasmic dynein tail mutation impairs motor processivity.

    Ori-McKenney KM, Xu J, Gross SP and Vallee RB

    Department of Pathology and Cell Biology, Columbia University. New York, NY 10032, USA.

    Mutations in the tail of the cytoplasmic dynein molecule have been reported to cause neurodegenerative disease in mice. The mutant mouse strain Legs at odd angles (Loa) has impaired retrograde axonal transport, but the molecular deficiencies in the mutant dynein molecule, and how they contribute to neurodegeneration, are unknown. To address these questions, we purified dynein from wild-type mice and the Legs at odd angles mutant mice. Using biochemical, single-molecule, and live-cell-imaging techniques, we find a marked inhibition of motor run-length in vitro and in vivo, and significantly altered motor domain coordination in the dynein from mutant mice. These results suggest a potential role for the dynein tail in motor function, and provide direct evidence for a link between single-motor processivity and disease.

    Funded by: NIGMS NIH HHS: GM008798-09, GM47434, R01 GM047434, R01 GM070676, R01GM070676, R37 GM047434, T32 GM008798

    Nature cell biology 2010;12;12;1228-34

  • Deficits in axonal transport precede ALS symptoms in vivo.

    Bilsland LG, Sahai E, Kelly G, Golding M, Greensmith L and Schiavo G

    Molecular NeuroPathobiology Laboratory, Cancer Research UK London Research Institute, London WC2A 3LY, United Kingdom.

    ALS is a fatal neurodegenerative disease characterized by selective motor neuron death resulting in muscle paralysis. Mutations in superoxide dismutase 1 (SOD1) are responsible for a subset of familial cases of ALS. Although evidence from transgenic mice expressing human mutant SOD1(G93A) suggests that axonal transport defects may contribute to ALS pathogenesis, our understanding of how these relate to disease progression remains unclear. Using an in vivo assay that allows the characterization of axonal transport in single axons in the intact sciatic nerve, we have identified clear axonal transport deficits in presymptomatic mutant mice. An impairment of axonal retrograde transport may therefore represent one of the earliest axonal pathologies in SOD1(G93A) mice, which worsens at an early symptomatic stage. A deficit in axonal transport may therefore be a key pathogenic event in ALS and an early disease indicator of motor neuron degeneration.

    Funded by: Cancer Research UK; Medical Research Council: G0601943

    Proceedings of the National Academy of Sciences of the United States of America 2010;107;47;20523-8

  • A point mutation in the dynein heavy chain gene leads to striatal atrophy and compromises neurite outgrowth of striatal neurons.

    Braunstein KE, Eschbach J, Ròna-Vörös K, Soylu R, Mikrouli E, Larmet Y, René F, Gonzalez De Aguilar JL, Loeffler JP, Müller HP, Bucher S, Kaulisch T, Niessen HG, Tillmanns J, Fischer K, Schwalenstöcker B, Kassubek J, Pichler B, Stiller D, Petersen A, Ludolph AC and Dupuis L

    Department of Neurology, University of Ulm, Ulm, Germany.

    The molecular motor dynein and its associated regulatory subunit dynactin have been implicated in several neurodegenerative conditions of the basal ganglia, such as Huntington's disease (HD) and Perry syndrome, an atypical Parkinson-like disease. This pathogenic role has been largely postulated from the existence of mutations in the dynactin subunit p150(Glued). However, dynactin is also able to act independently of dynein, and there is currently no direct evidence linking dynein to basal ganglia degeneration. To provide such evidence, we used here a mouse strain carrying a point mutation in the dynein heavy chain gene that impairs retrograde axonal transport. These mice exhibited motor and behavioural abnormalities including hindlimb clasping, early muscle weakness, incoordination and hyperactivity. In vivo brain imaging using magnetic resonance imaging showed striatal atrophy and lateral ventricle enlargement. In the striatum, altered dopamine signalling, decreased dopamine D1 and D2 receptor binding in positron emission tomography SCAN and prominent astrocytosis were observed, although there was no neuronal loss either in the striatum or substantia nigra. In vitro, dynein mutant striatal neurons displayed strongly impaired neuritic morphology. Altogether, these findings provide a direct genetic evidence for the requirement of dynein for the morphology and function of striatal neurons. Our study supports a role for dynein dysfunction in the pathogenesis of neurodegenerative disorders of the basal ganglia, such as Perry syndrome and HD.

    Human molecular genetics 2010;19;22;4385-98

  • The legs at odd angles (Loa) mutation in cytoplasmic dynein ameliorates mitochondrial function in SOD1G93A mouse model for motor neuron disease.

    El-Kadi AM, Bros-Facer V, Deng W, Philpott A, Stoddart E, Banks G, Jackson GS, Fisher EM, Duchen MR, Greensmith L, Moore AL and Hafezparast M

    Biochemistry and Biomedical Science, School of Life Sciences, University of Sussex, Brighton BN1 9QG, United Kingdom.

    Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal late-onset neurodegenerative disease. Familial cases of ALS (FALS) constitute approximately 10% of all ALS cases, and mutant superoxide dismutase 1 (SOD1) is found in 15-20% of FALS. SOD1 mutations confer a toxic gain of unknown function to the protein that specifically targets the motor neurons in the cortex and the spinal cord. We have previously shown that the autosomal dominant Legs at odd angles (Loa) mutation in cytoplasmic dynein heavy chain (Dync1h1) delays disease onset and extends the life span of transgenic mice harboring human mutant SOD1(G93A). In this study we provide evidence that despite the lack of direct interactions between mutant SOD1 and either mutant or wild-type cytoplasmic dynein, the Loa mutation confers significant reductions in the amount of mutant SOD1 protein in the mitochondrial matrix. Moreover, we show that the Loa mutation ameliorates defects in mitochondrial respiration and membrane potential observed in SOD1(G93A) motor neuron mitochondria. These data suggest that the Loa mutation reduces the vulnerability of mitochondria to the toxic effects of mutant SOD1, leading to improved mitochondrial function in SOD1(G93A) motor neurons.

    Funded by: Biotechnology and Biological Sciences Research Council: BB/D012309/1; Medical Research Council: G0500288, G0500865, G0601943, MC_U123170362; Wellcome Trust

    The Journal of biological chemistry 2010;285;24;18627-39

  • Dynein and kinesin regulate stress-granule and P-body dynamics.

    Loschi M, Leishman CC, Berardone N and Boccaccio GL

    Instituto Leloir, Avenida Patricias Argentinas 435, C1405BWE-Buenos Aires, Argentina.

    Stress granules (SGs) and P-bodies (PBs) are related cytoplasmic structures harboring silenced mRNAs. SGs assemble transiently upon cellular stress, whereas PBs are constitutive and are further induced by stress. Both foci are highly dynamic, with messenger ribonucleoproteins (mRNPs) and proteins rapidly shuttling in and out. Here, we show that impairment of retrograde transport by knockdown of mammalian dynein heavy chain 1 (DHC1) or bicaudal D1 (BicD1) inhibits SG formation and PB growth upon stress, without affecting protein-synthesis blockage. Conversely, impairment of anterograde transport by knockdown of kinesin-1 heavy chain (KIF5B) or kinesin light chain 1 (KLC1) delayed SG dissolution. Strikingly, SG dissolution is not required to restore translation. Simultaneous knockdown of dynein and kinesin reverted the effect of single knockdowns on both SGs and PBs, suggesting that a balance between opposing movements driven by these molecular motors governs foci formation and dissolution. Finally, we found that regulation of SG dynamics by dynein and kinesin is conserved in Drosophila.

    Funded by: FIC NIH HHS: 1R03 TW 006037-01A1

    Journal of cell science 2009;122;Pt 21;3973-82

  • A switch in retrograde signaling from survival to stress in rapid-onset neurodegeneration.

    Perlson E, Jeong GB, Ross JL, Dixit R, Wallace KE, Kalb RG and Holzbaur EL

    University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.

    Retrograde axonal transport of cellular signals driven by dynein is vital for neuronal survival. Mouse models with defects in the retrograde transport machinery, including the Loa mouse (point mutation in dynein) and the Tg(dynamitin) mouse (overexpression of dynamitin), exhibit mild neurodegenerative disease. Transport defects have also been observed in more rapidly progressive neurodegeneration, such as that observed in the SOD1(G93A) transgenic mouse model for familial amyotrophic lateral sclerosis (ALS). Here, we test the hypothesis that alterations in retrograde signaling lead to neurodegeneration. In vivo, in vitro, and live-cell imaging motility assays show misregulation of transport and inhibition of retrograde signaling in the SOD1(G93A) model. However, similar inhibition is also seen in the Loa and Tg(dynamitin) mouse models. Thus, slowing of retrograde signaling leads only to mild degeneration and cannot explain ALS etiology. To further pursue this question, we used a proteomics approach to investigate dynein-associated retrograde signaling. These data indicate a significant decrease in retrograde survival factors, including P-Trk (phospho-Trk) and P-Erk1/2, and an increase in retrograde stress factor signaling, including P-JNK (phosphorylated c-Jun N-terminal kinase), caspase-8, and p75(NTR) cleavage fragment in the SOD1(G93A) model; similar changes are not seen in the Loa mouse. Cocultures of motor neurons and glia expressing mutant SOD1 (mSOD1) in compartmentalized chambers indicate that inhibition of retrograde stress signaling is sufficient to block activation of cellular stress pathways and to rescue motor neurons from mSOD1-induced toxicity. Hence, a shift from survival-promoting to death-promoting retrograde signaling may be key to the rapid onset of neurodegeneration seen in ALS.

    Funded by: NINDS NIH HHS: R01 NS060698, R01 NS060698-02

    The Journal of neuroscience : the official journal of the Society for Neuroscience 2009;29;31;9903-17

  • Mutant glycyl-tRNA synthetase (Gars) ameliorates SOD1(G93A) motor neuron degeneration phenotype but has little affect on Loa dynein heavy chain mutant mice.

    Banks GT, Bros-Facer V, Williams HP, Chia R, Achilli F, Bryson JB, Greensmith L and Fisher EM

    Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.

    Background: In humans, mutations in the enzyme glycyl-tRNA synthetase (GARS) cause motor and sensory axon loss in the peripheral nervous system, and clinical phenotypes ranging from Charcot-Marie-Tooth neuropathy to a severe infantile form of spinal muscular atrophy. GARS is ubiquitously expressed and may have functions in addition to its canonical role in protein synthesis through catalyzing the addition of glycine to cognate tRNAs.

    We have recently described a new mouse model with a point mutation in the Gars gene resulting in a cysteine to arginine change at residue 201. Heterozygous Gars(C201R/+) mice have locomotor and sensory deficits. In an investigation of genetic mutations that lead to death of motor and sensory neurons, we have crossed the Gars(C201R/+) mice to two other mutants: the TgSOD1(G93A) model of human amyotrophic lateral sclerosis and the Legs at odd angles mouse (Dync1h1(Loa)) which has a defect in the heavy chain of the dynein complex. We found the Dync1h1(Loa/+);Gars(C201R/+) double heterozygous mice are more impaired than either parent, and this is may be an additive effect of both mutations. Surprisingly, the Gars(C201R) mutation significantly delayed disease onset in the SOD1(G93A);Gars(C201R/+) double heterozygous mutant mice and increased lifespan by 29% on the genetic background investigated.

    These findings raise intriguing possibilities for the study of pathogenetic mechanisms in all three mouse mutant strains.

    Funded by: Medical Research Council: G0500288, G0601943; Wellcome Trust

    PloS one 2009;4;7;e6218

  • Mice with a mutation in the dynein heavy chain 1 gene display sensory neuropathy but lack motor neuron disease.

    Dupuis L, Fergani A, Braunstein KE, Eschbach J, Holl N, Rene F, Gonzalez De Aguilar JL, Zoerner B, Schwalenstocker B, Ludolph AC and Loeffler JP

    INSERM, U692, Laboratoire de Signalisations Moléculaires et Neurodégénérescence, Strasbourg, F-67085, France. ldupuis@neurochem.u-strasbg.fr

    In neurons, cytoplasmic dynein functions as a molecular motor responsible for retrograde axonal transport. An impairment of axonal transport is thought to play a key role in the pathogenesis of neurodegenerative diseases such as amyotrophic lateral sclerosis, the most frequent motor neuron disease in the elderly. In this regard, previous studies described two heterozygous mouse strains bearing missense point mutations in the dynein heavy chain 1 gene that were reported to display late-onset progressive motor neuron degeneration. Here we show, however, that one of these mutant strains, the so-called Cra mice does not suffer from motor neuron loss, even in aged animals. Consistently, we did not observe electrophysiological or biochemical signs of muscle denervation, indicative of motor neuron disease. The "hindlimb clasping" phenotype of Cra mice could rather be due to the prominent degeneration of sensory neurons associated with a loss of muscle spindles. Altogether, these findings show that dynein heavy chain mutation triggers sensory neuropathy rather than motor neuron disease.

    Experimental neurology 2009;215;1;146-52

  • Dynein drives nuclear rotation during forward progression of motile fibroblasts.

    Levy JR and Holzbaur EL

    Department of Physiology, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6085, USA.

    During directed cell migration, the movement of the nucleus is coupled to the forward progression of the cell. The microtubule motor cytoplasmic dynein is required for both cell polarization and cell motility. Here, we investigate the mechanism by which dynein contributes to directed migration. Knockdown of dynein slows protrusion of the leading edge and causes defects in nuclear movements. The velocity of nuclear migration was decreased in dynein knockdown cells, and nuclei were mislocalized to the rear of motile cells. In control cells, we observed that wounding the monolayer stimulated a dramatic induction of nuclear rotations at the wound edge, reaching velocities up to 8.5 degrees/minute. These nuclear rotations were significantly inhibited in dynein knockdown cells. Surprisingly, centrosomes do not rotate in concert with the nucleus; instead, the centrosome remains stably positioned between the nucleus and the leading edge. Together, these results suggest that dynein contributes to migration in two ways: (1) maintaining centrosome centrality by tethering microtubule plus ends at the cortex; and (2) maintaining nuclear centrality by asserting force directly on the nucleus.

    Funded by: NIA NIH HHS: T32 AG 0025; NIGMS NIH HHS: GM 068591, R01 GM068591, R01 GM068591-04

    Journal of cell science 2008;121;Pt 19;3187-95

  • Mutant dynein (Loa) triggers proprioceptive axon loss that extends survival only in the SOD1 ALS model with highest motor neuron death.

    Ilieva HS, Yamanaka K, Malkmus S, Kakinohana O, Yaksh T, Marsala M and Cleveland DW

    Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093, USA.

    Dominant mutations in cytoplasmic dynein (Loa or Cra) have been reported to provoke selective, age-dependent killing of motor neurons, while paradoxically slowing degeneration and death of motor neurons in one mouse model of an inherited form of ALS. Examination of Loa animals reveals no degeneration of large caliber alpha-motor neurons beyond an age-dependent loss (initiating only after 18 months) that was comparable in Loa and wild-type littermates. Absence of Loa-mediated alpha-motor neuron loss contrasted with dramatic, sustained, mutant dynein-mediated postnatal loss of lumbar proprioceptive sensory axons, accompanied by decreased excitatory glutamatergic inputs to motor neurons. In mouse models of inherited ALS caused by mutations in superoxide dismutase (SOD1), mutant dynein modestly prolonged survival in the one mouse model with the most extensive motor neuron loss (SOD(G93A)) while showing marginal (SOD(G85R)) or no (SOD(G37R)) benefit in models with higher numbers of surviving motor neurons at end stage. These findings support a noncell autonomous, excitotoxic contribution from proprioceptive sensory neurons that modestly accelerates disease onset in inherited ALS.

    Funded by: NINDS NIH HHS: R37 NS 27036, R37 NS027036

    Proceedings of the National Academy of Sciences of the United States of America 2008;105;34;12599-604

  • Differential regulation of dynein and kinesin motor proteins by tau.

    Dixit R, Ross JL, Goldman YE and Holzbaur EL

    Department of Physiology and Pennsylvania Muscle Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.

    Dynein and kinesin motor proteins transport cellular cargoes toward opposite ends of microtubule tracks. In neurons, microtubules are abundantly decorated with microtubule-associated proteins (MAPs) such as tau. Motor proteins thus encounter MAPs frequently along their path. To determine the effects of tau on dynein and kinesin motility, we conducted single-molecule studies of motor proteins moving along tau-decorated microtubules. Dynein tended to reverse direction, whereas kinesin tended to detach at patches of bound tau. Kinesin was inhibited at about a tenth of the tau concentration that inhibited dynein, and the microtubule-binding domain of tau was sufficient to inhibit motor activity. The differential modulation of dynein and kinesin motility suggests that MAPs can spatially regulate the balance of microtubule-dependent axonal transport.

    Funded by: NIAMS NIH HHS: P01 AR051174, P01 AR051174-050002, P01-AR-051174; NIGMS NIH HHS: GM-48661, R01 GM048661, R01 GM048661-16

    Science (New York, N.Y.) 2008;319;5866;1086-9

  • Coordinated diurnal regulation of genes from the Dlk1-Dio3 imprinted domain: implications for regulation of clusters of non-paralogous genes.

    Labialle S, Yang L, Ruan X, Villemain A, Schmidt JV, Hernandez A, Wiltshire T, Cermakian N and Naumova AK

    Department of Obstetrics and Gynecology, McGill University, Montreal, QC, Canada.

    The functioning of the genome is tightly related to its architecture. Therefore, understanding the relationship between different regulatory mechanisms and the organization of chromosomal domains is essential for understanding genome regulation. The majority of imprinted genes are assembled into clusters, share common regulatory elements, and, hence, represent an attractive model for studies of regulation of clusters of non-paralogous genes. Here, we investigated the relationship between genomic imprinting and diurnal regulation of genes from the imprinted domain of mouse chromosome 12. We compared gene expression patterns in C57BL/6 mice and congenic mice that carry the imprinted region from a Mus musculus molossinus strain MOLF/Ei. In the C57BL/6 mice, a putative enhancer/oscillator regulated the expression of only Mico1/Mico1os, whereas in the congenic mice its influence was spread onto Rtl1as, Dio3 and Dio3os, i.e. the distal part of the imprinted domain, resulting in coordinated diurnal variation in expression of five genes. Using additional congenic strains we determined that in C57BL/6 the effect of the putative enhancer/oscillator was attenuated by a linked dominant trans-acting factor located in the distal portion of chromosome 12. Our data demonstrate that (i) in adult organs, mRNA levels of several imprinted genes vary during the day, (ii) genetic variation may remove constraints on the influence of an enhancer and lead to spreading of its effect onto neighboring genes, thereby generating genotype-dependent expression patterns and (iii) different regulatory mechanisms within the same domain act independently and do not seem to interfere with each other.

    Funded by: NICHD NIH HHS: HD042013, R01 HD042013; NIDDK NIH HHS: DK054716

    Human molecular genetics 2008;17;1;15-26

  • Cytoplasmic dynein could be key to understanding neurodegeneration.

    Banks GT and Fisher EM

    Department of Neurodegenerative Disease, Institute of Neurology, Queen Square, London WC1N 3BG, UK. g.banks@prion.ucl.ac.uk.

    A new mouse mutation, Sprawling, highlights an essential role for the dynein heavy chain in sensory neuron function, but it lacks the ability of other known heavy-chain mutations to ameliorate neurodegeneration due to defective superoxide dismutase.

    Funded by: Medical Research Council: G0500288; Wellcome Trust

    Genome biology 2008;9;3;214

  • Proprioceptive sensory neuropathy in mice with a mutation in the cytoplasmic Dynein heavy chain 1 gene.

    Chen XJ, Levedakou EN, Millen KJ, Wollmann RL, Soliven B and Popko B

    Jack Miller Center for Peripheral Neuropathy and Department of Neurology, The University of Chicago, Chicago, Illinois 60637, USA.

    Mice heterozygous for the radiation-induced Sprawling (Swl) mutation display an early-onset sensory neuropathy with muscle spindle deficiency. The lack of an H reflex despite normal motor nerve function in the hindlimbs of these mutants strongly suggests defective proprioception. Immunohistochemical analyses reveal that proprioceptive sensory neurons are severely compromised in the lumbar dorsal root ganglia of newborn Swl/+ mice, whereas motor neuron numbers remain unaltered even in aged animals. We have used positional cloning to identify a nine base-pair deletion in the cytoplasmic dynein heavy chain 1 gene (Dync1h1) in this mutant. Furthermore, we demonstrate that Loa/+ mice, which have previously been shown to carry a missense point mutation in Dync1h1 that results in late-onset motor neuron loss, also present with a severe, early-onset proprioceptive sensory neuropathy. Interestingly, in contrast to the Loa mutation, the Swl mutation does not delay disease progression in a motor neuron disease mouse model overexpressing a human mutant superoxide dismutase (SOD1(G93A)) transgene. Together, we provide in vivo evidence that distinct mutations in cytoplasmic dynein can either result in a pure sensory neuropathy or in a sensory neuropathy with motor neuron involvement.

    Funded by: NINDS NIH HHS: R01 NS044262

    The Journal of neuroscience : the official journal of the Society for Neuroscience 2007;27;52;14515-24

  • Dynein modifiers in C. elegans: light chains suppress conditional heavy chain mutants.

    O'Rourke SM, Dorfman MD, Carter JC and Bowerman B

    Institute of Molecular Biology, University of Oregon, Eugene, Oregon, United States of America. seanor@molbio.uoregon.edu

    Cytoplasmic dynein is a microtubule-dependent motor protein that functions in mitotic cells during centrosome separation, metaphase chromosome congression, anaphase spindle elongation, and chromosome segregation. Dynein is also utilized during interphase for vesicle transport and organelle positioning. While numerous cellular processes require cytoplasmic dynein, the mechanisms that target and regulate this microtubule motor remain largely unknown. By screening a conditional Caenorhabditis elegans cytoplasmic dynein heavy chain mutant at a semipermissive temperature with a genome-wide RNA interference library to reduce gene functions, we have isolated and characterized twenty dynein-specific suppressor genes. When reduced in function, these genes suppress dynein mutants but not other conditionally mutant loci, and twelve of the 20 specific suppressors do not exhibit sterile or lethal phenotypes when their function is reduced in wild-type worms. Many of the suppressor proteins, including two dynein light chains, localize to subcellular sites that overlap with those reported by others for the dynein heavy chain. Furthermore, knocking down any one of four putative dynein accessory chains suppresses the conditional heavy chain mutants, suggesting that some accessory chains negatively regulate heavy chain function. We also identified 29 additional genes that, when reduced in function, suppress conditional mutations not only in dynein but also in loci required for unrelated essential processes. In conclusion, we have identified twenty genes that in many cases are not essential themselves but are conserved and when reduced in function can suppress conditionally lethal C. elegans cytoplasmic dynein heavy chain mutants. We conclude that conserved but nonessential genes contribute to dynein function during the essential process of mitosis.

    Funded by: NIGMS NIH HHS: GM049869, R01 GM049869

    PLoS genetics 2007;3;8;e128

  • Reaching and grasping phenotypes in the mouse (Mus musculus): a characterization of inbred strains and mutant lines.

    Tucci V, Achilli F, Blanco G, Lad HV, Wells S, Godinho S and Nolan PM

    MRC Mammalian Genetics Unit, Harwell, Didcot, Oxfordshire OX11 0RD, UK. v.tucci@har.mrc.ac.uk

    Skilled movements, such as reaching and grasping, have classically been considered as originating in the primate lineage. For this reason, the use of rodents to investigate the genetic and molecular machinery of reaching and grasping has been limited in research. A few studies in rodents have now shown that these movements are not exclusive to primates. Here we present a new test, the Mouse Reaching and Grasping (MoRaG) performance scale, intended to help researchers in the characterization of these motor behaviors in the mouse. Within the MoRaG test battery we identified early phenotypes for the characterization of motor neurone (Tg[SOD1-G93A](dl)1Gur mice) and neurodegenerative (TgN(HD82Gln)81Dbo transgenic mice) disease models in addition to specific motor deficits associated with aging (C3H/HeH inbred strain). We conclude that the MoRaG test can be used to further investigate complex neuromuscular, neurological, neurodegenerative and behavioral disorders. Moreover, our study supports the validity of the mouse as a model for reaching and grasping studies.

    Funded by: Medical Research Council: MC_U142684168, MC_U142684172, MC_U142684173, MC_U142684175

    Neuroscience 2007;147;3;573-82

  • Potential target genes of EMX2 include Odz/Ten-M and other gene families with implications for cortical patterning.

    Li H, Bishop KM and O'Leary DD

    Molecular Neurobiology Laboratory, The Salk Institute, 10010 N. Torrey Pines Rd., La Jolla, CA 92037, USA.

    EMX2 and PAX6 are expressed by cortical progenitors and specify area patterning. We used representational difference analysis (RDA) to compare expressed RNAs from wild type and Emx2-/- cortex and identified 41 unique clones. Using secondary screening by in situ hybridization, we selected five genes for further analysis, Cdk4, Cofilin1, Crmp1, ME2, and Odz4, involved in neuronal proliferation, differentiation, migration, and axon guidance. Each exhibits differential expression in wild type cortex. Odz4 is one of four members of a vertebrate gene family homologous to the Drosophila pair-rule patterning gene, Odd Oz (Odz), a transmembrane receptor. We show that Odz genes are expressed in complementary patterns in cortex, as well as in nuclei-specific patterns in thalamus that relates to their area-unique cortical expression. In addition, each of the genes analyzed shows different expression patterns in wild type cortex, Emx2, and Pax6 mutant cortex, consistent with potential roles in area patterning. These findings identify potential targets of EMX2 that might account for its function and the defects in Emx2-/- cortex, and suggest that the Odz family of transmembrane proteins influences cortical area patterning downstream to EMX2 and PAX6.

    Funded by: NINDS NIH HHS: R37 NS31558

    Molecular and cellular neurosciences 2006;33;2;136-49

  • The murine Dnali1 gene encodes a flagellar protein that interacts with the cytoplasmic dynein heavy chain 1.

    Rashid S, Breckle R, Hupe M, Geisler S, Doerwald N and Neesen J

    Institute of Human Genetics, University of Goettingen, Goettingen, Germany.

    Axonemal dyneins are large motor protein complexes generating the force for the movement of eukaryotic cilia and flagella. Disruption of axonemal dynein function leads to loss of ciliary motility and can result in male infertility or lateralization defects. Here, we report the molecular analysis of a murine gene encoding the dynein axonemal light intermediate chain Dnali1. The Dnali1 gene is localized on chromosome 4 and consists of six exons. It is predominantly expressed within the testis but at a lower level Dnali1 transcripts were also observed in different murine tissues, which exhibit cilia. Two transcript variants were detected, generated by the usage of two alternative polyadenylation signals within exon 6. Antibodies were raised against a GST-Dnali1 fusion protein and used to localize Dnali1 within differentiating male germ cells. Dnali1 is strongly expressed in spermatids but was also detected in spermatocytes. Moreover, the Dnali1 protein was localized in cilia of the trachea as well as in flagella of mature sperm supporting its function as an axonemal dynein. To identify putative Dnali1 interacting polypeptides, a yeast two-hybrid approach was performed using a murine testicular cDNA library. By this assay, the C-terminal part of the cytoplasmic dynein heavy chain 1 was identified as a putative interacting polypeptide of Dnali1. The interaction between the axonemal and the cytoplasmic dynein fragments was proven by co-immuno and co-localization experiments.

    Molecular reproduction and development 2006;73;6;784-94

  • A dynein mutation attenuates motor neuron degeneration in SOD1(G93A) mice.

    Teuchert M, Fischer D, Schwalenstoecker B, Habisch HJ, Böckers TM and Ludolph AC

    Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081 Ulm, Germany.

    Cu/Zn SOD1(G93A) transgenic mice develop phenotypical hallmarks of ALS and serve therefore as an established model to study the molecular mechanisms underlying this disease. Recent reports demonstrate that mutations in the motor protein dynein in Legs at odd angles (Loa) and Cramping (Cra1) mice lead to similar but milder phenotypes. Surprisingly, double transgenic mice (Loa/SOD1(G93A)) have been recently shown to attenuate rather than to accelerate the phenotypical expression of motor neuron degeneration. These results raise the question whether other functional relevant mutations in dynein cause a similar effect. To address this question, we have cross-bred SOD1(G93A) with Cra1/+ mice. These double transgenic mice show an attenuated decline of both motor activity and body weight and an increase of survival time compared to SOD1(G93A) mice. Thus, this study confirms that mechanisms associated with dynein such as retrograde axonal transport may play an important role in SOD1(G93A-) toxicity on motor neurons.

    Experimental neurology 2006;198;1;271-4

  • High-resolution map and imprinting analysis of the Gtl2-Dnchc1 domain on mouse chromosome 12.

    Tierling S, Dalbert S, Schoppenhorst S, Tsai CE, Oliger S, Ferguson-Smith AC, Paulsen M and Walter J

    Genetik/Epigenetik, FR 8.3 Biowissenschaften, Universität des Saarlandes, Postfach 151150, D-66041 Saarbrücken, Germany.

    The imprinted Dlk1-Dio3 region on mouse chromosome 12 contains six imprinted genes and a number of maternally expressed snoRNAs and miRNAs. Here we present a high-resolution sequence analysis of the 1.1-Mb segment telomeric to Gtl2 in mouse and a homology comparison to the human. Ppp2r5c and Dnchc1 at the telomeric end of the analyzed sequence are biallelically expressed, suggesting that the imprinted domain does not extend beyond the paternally expressed Dio3 gene. RT-PCR experiments support the predicted presence of a maternally expressed intergenic transcript(s) encompassing Gtl2, Rian, and Mirg. These maternally expressed genes, and also the intergenic transcript(s), show pronounced expression in the adult mouse brain, whereas the paternally transcribed Dio3 and the nonimprinted Ppp2r5c and Dnchc1 are expressed in different tissues. Hence, tissue-specific coregulation of maternally expressed genes might be an important feature of this domain.

    Funded by: Medical Research Council: G0400156

    Genomics 2006;87;2;225-35

  • Genetic analysis of the cytoplasmic dynein subunit families.

    Pfister KK, Shah PR, Hummerich H, Russ A, Cotton J, Annuar AA, King SM and Fisher EM

    Department of Cell Biology, School of Medicine, University of Virginia, Charlottesville, Virginia, USA. kkp9w@virginia.edu

    Cytoplasmic dyneins, the principal microtubule minus-end-directed motor proteins of the cell, are involved in many essential cellular processes. The major form of this enzyme is a complex of at least six protein subunits, and in mammals all but one of the subunits are encoded by at least two genes. Here we review current knowledge concerning the subunits, their interactions, and their functional roles as derived from biochemical and genetic analyses. We also carried out extensive database searches to look for new genes and to clarify anomalies in the databases. Our analysis documents evolutionary relationships among the dynein subunits of mammals and other model organisms, and sheds new light on the role of this diverse group of proteins, highlighting the existence of two cytoplasmic dynein complexes with distinct cellular roles.

    Funded by: Medical Research Council: MC_U123160651; NIGMS NIH HHS: GM51293, GM63548, R01 GM051293, R01 GM063548

    PLoS genetics 2006;2;1;e1

  • Aberrant regulation of imprinted gene expression in Gtl2lacZ mice.

    Sekita Y, Wagatsuma H, Irie M, Kobayashi S, Kohda T, Matsuda J, Yokoyama M, Ogura A, Schuster-Gossler K, Gossler A, Ishino F and Kaneko-Ishino T

    Department of Epigenetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.

    The imprinted region on mouse distal chromosome 12 covers about 1 Mb and contains at least three paternally expressed genes (Pegs: Peg9/Dlk1, Peg11/Rtl1, and Dio3) and four maternally expressed genes (Megs: Meg3/Gtl2, antiPeg11/antiRlt1, Meg8/Rian, and Meg9/Mirg). Gtl2(lacZ) (Gene trap locus 2) mice have a transgene (TG) insertion 2.3 kb upstream from the Meg3/Gtl2 promoter and show about 40% growth retardation when the TG-inserted allele is paternally derived. Quantitative RT-PCR experiments showed that the expression levels of Pegs in this region were reduced below 50%. These results are consistent with the observed phenotype in Gtl2lacZ mice, because at least two Pegs(Peg9/Dlk1 and Dio3) have growth-promoting effects. The aberrant induction of Megs from silent paternal alleles was also observed in association with changes in the DNA methylation level of a differentially methylated region (DMR) located around Meg3/Gtl2 exon 1. Interestingly, a 60 approximately 80% reduction in all Megs was observed when the TG was maternally derived, although the pups showed no apparent growth or morphological abnormalities. Therefore, the paternal or maternal inheritance of the TG results in the down-regulation in cis of either Pegs or Megs, respectively, suggesting that the TG insertion influences the mechanism regulating the entire imprinted region.

    Cytogenetic and genome research 2006;113;1-4;223-9

  • A proteomics strategy for the enrichment of receptor-associated complexes.

    Cross M, Nguyen T, Bogdanoska V, Reynolds E and Hamilton JA

    University of Melbourne, Department of Medicine, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.

    Multimeric protein complexes are important for cell function and are being identified by proteomics approaches. Enrichment strategies, such as those employing affinity matrices, are required for the characterization of such complexes, for example, those containing growth factor receptors. The receptor for the macrophage lineage growth factor, macrophage-colony stimulating factor (M-CSF or CSF-1), is the tyrosine kinase, c-Fms. There is evidence that the CSF-1 receptor (CSF-1R) forms distinct multimeric complexes involving autophosphorylated tyrosines in its cytoplasmic region; however, these complexes are difficult to identify by immunoprecipitation, making enrichment necessary. We report here the use of a tyrosine-phosphorylated, GST-fusion construct of the entire CSF-1R cytoplasmic region to characterize proteins putatively associating with the activated CSF-1R. Besides signalling molecules known to associate with the receptor or be involved in CSF-1R-dependent signalling, mass spectrometry identified a number of other molecules binding to the construct. So far among these candidate proteins, dynein, claudin and silencer of death domains co-immunoprecipitated with the CSF-1R, suggesting association. This affinity matrix method, using an entire cytoplasmic region, may have relevance for other growth factor receptors.

    Proteomics 2005;5;18;4754-63

  • Cytoplasmic dynein nomenclature.

    Pfister KK, Fisher EM, Gibbons IR, Hays TS, Holzbaur EL, McIntosh JR, Porter ME, Schroer TA, Vaughan KT, Witman GB, King SM and Vallee RB

    Department of Cell Biology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA. kkp9w@virginia.edu

    A variety of names has been used in the literature for the subunits of cytoplasmic dynein complexes. Thus, there is a strong need for a more definitive consensus statement on nomenclature. This is especially important for mammalian cytoplasmic dyneins, many subunits of which are encoded by multiple genes. We propose names for the mammalian cytoplasmic dynein subunit genes and proteins that reflect the phylogenetic relationships of the genes and the published studies clarifying the functions of the polypeptides. This nomenclature recognizes the two distinct cytoplasmic dynein complexes and has the flexibility to accommodate the discovery of new subunits and isoforms.

    Funded by: NIGMS NIH HHS: R01 GM030626, R01 GM060560, R01 GM060560-05

    The Journal of cell biology 2005;171;3;411-3

  • Dynein mutations impair autophagic clearance of aggregate-prone proteins.

    Ravikumar B, Acevedo-Arozena A, Imarisio S, Berger Z, Vacher C, O'Kane CJ, Brown SD and Rubinsztein DC

    Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2XY, UK.

    Mutations that affect the dynein motor machinery are sufficient to cause motor neuron disease. It is not known why there are aggregates or inclusions in affected tissues in mice with such mutations and in most forms of human motor neuron disease. Here we identify a new mechanism of inclusion formation by showing that decreased dynein function impairs autophagic clearance of aggregate-prone proteins. We show that mutations of the dynein machinery enhanced the toxicity of the mutation that causes Huntington disease in fly and mouse models. Furthermore, loss of dynein function resulted in premature aggregate formation by mutant huntingtin and increased levels of the autophagosome marker LC3-II in both cell culture and mouse models, compatible with impaired autophagosome-lysosome fusion.

    Funded by: Medical Research Council: G0000872

    Nature genetics 2005;37;7;771-6

  • The SOD1 transgene in the G93A mouse model of amyotrophic lateral sclerosis lies on distal mouse chromosome 12.

    Achilli F, Boyle S, Kieran D, Chia R, Hafezparast M, Martin JE, Schiavo G, Greensmith L, Bickmore W and Fisher EM

    Department of Neurodegenerative Disease, Institute of Neurology, Queen Square, London, UK.

    The SOD1G93A transgenic mouse strain which carries a human mutant Cu/Zn superoxide dismutase transgene array is a widely studied model of amyotrophic lateral sclerosis. These mice have been used in many breeding experiments to look for interactions with other loci, including transgenic and gene targeted mutations. Therefore, we decided to map the site of the transgene insertion as this may affect the outcome of such breeding experiments. In a fluorescence in situ hybridization experiment we determined that the SOD1G93A transgene insertion site lies on distal mouse chromosome 12. This chromosome also carries the 'Legs at odd angles' locus, which is an entirely unrelated mutation in the dynein heavy chain gene that we have been studying. We have analysed data from a SOD1G93AxLoa cross and determined that the site of the transgene insertion lies proximal of the dynein heavy chain gene on mouse chromosome 12.

    Funded by: Medical Research Council: G0300854

    Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases 2005;6;2;111-4

  • Prion disease incubation time is not affected in mice heterozygous for a dynein mutation.

    Hafezparast M, Brandner S, Linehan J, Martin JE, Collinge J and Fisher EM

    Department of Neurodegenerative Disease, Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK. m.hafezparast@sussex.ac.uk

    A mechanism for transmission of the infectious prions from the peripheral nerve ends to the central nervous system is thought to involve neuronal anterograde and retrograde transport systems. Cytoplasmic dynein is the major retrograde transport molecular motor whose function is impaired in the Legs at odd angles (Loa) mouse due to a point mutation in the cytoplasmic dynein heavy chain subunit. Loa is a dominant trait which causes neurodegeneration and progressive motor function deficit in the heterozygotes. To investigate the role of cytoplasmic dynein in the transmission of prions within neurons, we inoculated heterozygous Loa and wild type littermates with mouse-adapted scrapie prions intracerebrally and intraperitonially, and determined the incubation period to onset of clinical prion disease. Our data indicate that the dynein mutation in the heterozygous state does not affect prion disease incubation time or its neuropathology in Loa mice.

    Funded by: Biotechnology and Biological Sciences Research Council: BBS/B/0627X

    Biochemical and biophysical research communications 2005;326;1;18-22

  • Wnk1 kinase deficiency lowers blood pressure in mice: a gene-trap screen to identify potential targets for therapeutic intervention.

    Zambrowicz BP, Abuin A, Ramirez-Solis R, Richter LJ, Piggott J, BeltrandelRio H, Buxton EC, Edwards J, Finch RA, Friddle CJ, Gupta A, Hansen G, Hu Y, Huang W, Jaing C, Key BW, Kipp P, Kohlhauff B, Ma ZQ, Markesich D, Payne R, Potter DG, Qian N, Shaw J, Schrick J, Shi ZZ, Sparks MJ, Van Sligtenhorst I, Vogel P, Walke W, Xu N, Zhu Q, Person C and Sands AT

    Lexicon Genetics, 8800 Technology Forest Place, The Woodlands, TX 77381, USA. brian@lexgen.com

    The availability of both the mouse and human genome sequences allows for the systematic discovery of human gene function through the use of the mouse as a model system. To accelerate the genetic determination of gene function, we have developed a sequence-tagged gene-trap library of >270,000 mouse embryonic stem cell clones representing mutations in approximately 60% of mammalian genes. Through the generation and phenotypic analysis of knockout mice from this resource, we are undertaking a functional screen to identify genes regulating physiological parameters such as blood pressure. As part of this screen, mice deficient for the Wnk1 kinase gene were generated and analyzed. Genetic studies in humans have shown that large intronic deletions in WNK1 lead to its overexpression and are responsible for pseudohypoaldosteronism type II, an autosomal dominant disorder characterized by hypertension, increased renal salt reabsorption, and impaired K+ and H+ excretion. Consistent with the human genetic studies, Wnk1 heterozygous mice displayed a significant decrease in blood pressure. Mice homozygous for the Wnk1 mutation died during embryonic development before day 13 of gestation. These results demonstrate that Wnk1 is a regulator of blood pressure critical for development and illustrate the utility of a functional screen driven by a sequence-based mutagenesis approach.

    Proceedings of the National Academy of Sciences of the United States of America 2003;100;24;14109-14

  • A study of the nature of embryonic lethality in LIS1-/- mice.

    Cahana A, Jin XL, Reiner O, Wynshaw-Boris A and O'Neill C

    Human Reproduction Unit, Department of Physiology, University of Sydney, Royal North Shore Hospital, St. Leonards, New South Wales, Australia.

    Homozygous deletion of the Lis1 gene (Lis1(-/-)) in mouse resulted in early embryonic lethality immediately after embryo implantation by an undefined mechanism. We seek to define the nature of this demise. LIS1 (pafah1b1) is a 46 kDa protein with seven tryptophan-aspartate (WD) repeats. It docks with many proteins and has been implicated in microtubular function, cell division, intercellular transport, and nuclear and cellular motility. Combined Western and quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analyses showed that LIS1 expression from the blastocyst stage required new transcription from the embryonic genome. Consequently, the death of post-implantation embryos may not reflect the first time during development that LIS1 was required, rather, it may reflect the first time following depletion of gametic stores that its actions were essential. Following culture of blastocysts in vitro for 96 hr the inner cell mass (ICM) of null embryos were significantly smaller than ICM of wild-type siblings. Normal blastocyst outgrowths after 96-hr culture had high levels of LIS1 expression in the outer cells of developing ICM and extensive expression in trophoblast cells. Lis1(-/-) embryos had significantly smaller trophoblast nuclei than wild-type embryos. The results show that LIS1 expression is required for the continued normal development of the ICM and optimal trophoblast giant cell formation.

    Molecular reproduction and development 2003;66;2;134-42

  • A large-scale, gene-driven mutagenesis approach for the functional analysis of the mouse genome.

    Hansen J, Floss T, Van Sloun P, Füchtbauer EM, Vauti F, Arnold HH, Schnütgen F, Wurst W, von Melchner H and Ruiz P

    Institute of Developmental Genetics, GSF-National Research Center for Environment and Health, D-85764 Neuherberg, Germany.

    A major challenge of the postgenomic era is the functional characterization of every single gene within the mammalian genome. In an effort to address this challenge, we assembled a collection of mutations in mouse embryonic stem (ES) cells, which is the largest publicly accessible collection of such mutations to date. Using four different gene-trap vectors, we generated 5,142 sequences adjacent to the gene-trap integration sites (gene-trap sequence tags; http://genetrap.de) from >11,000 ES cell clones. Although most of the gene-trap vector insertions occurred randomly throughout the genome, we found both vector-independent and vector-specific integration "hot spots." Because >50% of the hot spots were vector-specific, we conclude that the most effective way to saturate the mouse genome with gene-trap insertions is by using a combination of gene-trap vectors. When a random sample of gene-trap integrations was passaged to the germ line, 59% (17 of 29) produced an observable phenotype in transgenic mice, a frequency similar to that achieved by conventional gene targeting. Thus, gene trapping allows a large-scale and cost-effective production of ES cell clones with mutations distributed throughout the genome, a resource likely to accelerate genome annotation and the in vivo modeling of human disease.

    Proceedings of the National Academy of Sciences of the United States of America 2003;100;17;9918-22

  • Mutations in dynein link motor neuron degeneration to defects in retrograde transport.

    Hafezparast M, Klocke R, Ruhrberg C, Marquardt A, Ahmad-Annuar A, Bowen S, Lalli G, Witherden AS, Hummerich H, Nicholson S, Morgan PJ, Oozageer R, Priestley JV, Averill S, King VR, Ball S, Peters J, Toda T, Yamamoto A, Hiraoka Y, Augustin M, Korthaus D, Wattler S, Wabnitz P, Dickneite C, Lampel S, Boehme F, Peraus G, Popp A, Rudelius M, Schlegel J, Fuchs H, Hrabe de Angelis M, Schiavo G, Shima DT, Russ AP, Stumm G, Martin JE and Fisher EM

    Department of Neurodegenerative Disease, Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.

    Degenerative disorders of motor neurons include a range of progressive fatal diseases such as amyotrophic lateral sclerosis (ALS), spinal-bulbar muscular atrophy (SBMA), and spinal muscular atrophy (SMA). Although the causative genetic alterations are known for some cases, the molecular basis of many SMA and SBMA-like syndromes and most ALS cases is unknown. Here we show that missense point mutations in the cytoplasmic dynein heavy chain result in progressive motor neuron degeneration in heterozygous mice, and in homozygotes this is accompanied by the formation of Lewy-like inclusion bodies, thus resembling key features of human pathology. These mutations exclusively perturb neuron-specific functions of dynein.

    Science (New York, N.Y.) 2003;300;5620;808-12

  • Prediction of the coding sequences of mouse homologues of KIAA gene: II. The complete nucleotide sequences of 400 mouse KIAA-homologous cDNAs identified by screening of terminal sequences of cDNA clones randomly sampled from size-fractionated libraries.

    Okazaki N, Kikuno R, Ohara R, Inamoto S, Aizawa H, Yuasa S, Nakajima D, Nagase T, Ohara O and Koga H

    Kazusa DNA Research Institute, 2-6-7 Kazusa-Kamatari, Kisarazu, Chiba 292-0818, Japan.

    We have accumulated information of the coding sequences of uncharacterized human genes, which are known as KIAA genes, and the number of these genes exceeds 2000 at present. As an extension of this sequencing project, we recently have begun to accumulate mouse KIAA-homologous cDNAs, because it would be useful to prepare a set of human and mouse homologous cDNA pairs for further functional analysis of the KIAA genes. We herein present the entire sequences of 400 mouse KIAA cDNA clones and 4 novel cDNA clones which were incidentally identified during this project. Most of clones entirely sequenced in this study were selected by computer-assisted analysis of terminal sequences of the cDNAs. The average size of the 404 cDNA sequences reached 5.3 kb and that of the deduced amino acid sequences from these cDNAs was 868 amino acid residues. The results of sequence analyses of these clones showed that single mouse KIAA cDNAs bridged two different human KIAA cDNAs in some cases, which indicated that these two human KIAA cDNAs were derived from single genes although they had been supposed to originate from different genes. Furthermore, we successfully mapped all the mouse KIAA cDNAs along the genome using a recently published mouse genome draft sequence.

    DNA research : an international journal for rapid publication of reports on genes and genomes 2003;10;1;35-48

  • BayGenomics: a resource of insertional mutations in mouse embryonic stem cells.

    Stryke D, Kawamoto M, Huang CC, Johns SJ, King LA, Harper CA, Meng EC, Lee RE, Yee A, L'Italien L, Chuang PT, Young SG, Skarnes WC, Babbitt PC and Ferrin TE

    Department of Pharmaceutical Chemistry, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA.

    The BayGenomics gene-trap resource (http://baygenomics.ucsf.edu) provides researchers with access to thousands of mouse embryonic stem (ES) cell lines harboring characterized insertional mutations in both known and novel genes. Each cell line contains an insertional mutation in a specific gene. The identity of the gene that has been interrupted can be determined from a DNA sequence tag. Approximately 75% of our cell lines contain insertional mutations in known mouse genes or genes that share strong sequence similarities with genes that have been identified in other organisms. These cell lines readily transmit the mutation to the germline of mice and many mutant lines of mice have already been generated from this resource. BayGenomics provides facile access to our entire database, including sequence tags for each mutant ES cell line, through the World Wide Web. Investigators can browse our resource, search for specific entries, download any portion of our database and BLAST sequences of interest against our entire set of cell line sequence tags. They can then obtain the mutant ES cell line for the purpose of generating knockout mice.

    Funded by: NCRR NIH HHS: P41 RR001081, P41 RR01081; NHLBI NIH HHS: U01 HL066621, U01 HL66621

    Nucleic acids research 2003;31;1;278-81

  • An integrated genetic, radiation hybrid, physical and transcription map of a region of distal mouse chromosome 12, including an imprinted locus and the 'Legs at odd angles' (Loa) mutation.

    Witherden AS, Hafezparast M, Nicholson SJ, Ahmad-Annuar A, Bermingham N, Arac D, Rankin J, Iravani M, Ball S, Peters J, Martin JE, Huntley D, Hummerich H, Sergot M and Fisher EM

    Department of Neurogenetics, Imperial College, W2 1PG, London, UK.

    A variety of loci with interesting patterns of regulation such as imprinted expression, and critical functions such as involvement in tumour necrosis factor pathways, map to a distal portion of mouse chromosome 12. This region also contains disease related loci including the 'Legs at odd angles' mutation (Loa) that we are pursuing in a positional cloning project. To further define the region and prepare for comparative sequencing projects, we have produced genetic, radiation hybrid, physical and transcript maps of the region, with probes providing anchors between the maps. We show a summary of 95 markers and 91 genomic clones that has enabled us to identify 18 transcripts including new genes and candidates for Loa which will help in future studies of gene context and regulation.

    Gene 2002;283;1-2;71-82

  • SHIRPA, a protocol for behavioral assessment: validation for longitudinal study of neurological dysfunction in mice.

    Rogers DC, Peters J, Martin JE, Ball S, Nicholson SJ, Witherden AS, Hafezparast M, Latcham J, Robinson TL, Quilter CA and Fisher EM

    Neuroscience Research, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow, CM19 5AW, Essex, UK. Derek_C_Rogers@sbphrd.com

    Mouse models of neurological abnormalities are only valuable if accurately assessed. The three-stage SHIRPA procedure is used for the standardised assessment of mouse phenotype and has been reported in a high throughput experiment in which different mutants were ascertained at one age point using stage 1 of the protocol. In this study we have validated SHIRPA using a large cohort with one single mutation, 'legs at odd angles that causes neurological dysfunction. The cohort aged from 1 to 16 months during this study and this is the first longitudinal SHIRPA analysis.

    Neuroscience letters 2001;306;1-2;89-92

  • The effects of aging on gene expression in the hypothalamus and cortex of mice.

    Jiang CH, Tsien JZ, Schultz PG and Hu Y

    Genomics Institute of the Novartis Research Foundation, 3115 Merryfield Row, San Diego, CA 92121, USA.

    A better understanding of the molecular effects of aging in the brain may help to reveal important aspects of organismal aging, as well as processes that lead to age-related brain dysfunction. In this study, we have examined differences in gene expression in the hypothalamus and cortex of young and aged mice by using high-density oligonucleotide arrays. A number of key genes involved in neuronal structure and signaling are differentially expressed in both the aged hypothalamus and cortex, including synaptotagmin I, cAMP-dependent protein kinase C beta, apolipoprotein E, protein phosphatase 2A, and prostaglandin D. Misregulation of these proteins may contribute to age-related memory deficits and neurodegenerative diseases. In addition, many proteases that play essential roles in regulating neuropeptide metabolism, amyloid precursor protein processing, and neuronal apoptosis are up-regulated in the aged brain and likely contribute significantly to brain aging. Finally, a subset of these genes whose expression is affected by aging are oppositely affected by exposure of mice to an enriched environment, suggesting that these genes may play important roles in learning and memory.

    Proceedings of the National Academy of Sciences of the United States of America 2001;98;4;1930-4

  • Genome-wide expression profiling of mid-gestation placenta and embryo using a 15,000 mouse developmental cDNA microarray.

    Tanaka TS, Jaradat SA, Lim MK, Kargul GJ, Wang X, Grahovac MJ, Pantano S, Sano Y, Piao Y, Nagaraja R, Doi H, Wood WH, Becker KG and Ko MS

    Laboratory of Genetics and DNA Array Unit, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224-6820, USA.

    cDNA microarray technology has been increasingly used to monitor global gene expression patterns in various tissues and cell types. However, applications to mammalian development have been hampered by the lack of appropriate cDNA collections, particularly for early developmental stages. To overcome this problem, a PCR-based cDNA library construction method was used to derive 52,374 expressed sequence tags from pre- and peri-implantation embryos, embryonic day (E) 12.5 female gonad/mesonephros, and newborn ovary. From these cDNA collections, a microarray representing 15,264 unique genes (78% novel and 22% known) was assembled. In initial applications, the divergence of placental and embryonic gene expression profiles was assessed. At stage E12.5 of development, based on triplicate experiments, 720 genes (6.5%) displayed statistically significant differences in expression between placenta and embryo. Among 289 more highly expressed in placenta, 61 placenta-specific genes encoded, for example, a novel prolactin-like protein. The number of genes highly expressed (and frequently specific) for placenta has thereby been increased 5-fold over the total previously reported, illustrating the potential of the microarrays for tissue-specific gene discovery and analysis of mammalian developmental programs.

    Proceedings of the National Academy of Sciences of the United States of America 2000;97;16;9127-32

  • Genome-wide, large-scale production of mutant mice by ENU mutagenesis.

    Hrabé de Angelis MH, Flaswinkel H, Fuchs H, Rathkolb B, Soewarto D, Marschall S, Heffner S, Pargent W, Wuensch K, Jung M, Reis A, Richter T, Alessandrini F, Jakob T, Fuchs E, Kolb H, Kremmer E, Schaeble K, Rollinski B, Roscher A, Peters C, Meitinger T, Strom T, Steckler T, Holsboer F, Klopstock T, Gekeler F, Schindewolf C, Jung T, Avraham K, Behrendt H, Ring J, Zimmer A, Schughart K, Pfeffer K, Wolf E and Balling R

    Institute of Experimental Genetics, GSF Research Center for Environment and Health, Neuherberg, Germany. hrabe@gsf.de

    In the post-genome era, the mouse will have a major role as a model system for functional genome analysis. This requires a large number of mutants similar to the collections available from other model organisms such as Drosophila melanogaster and Caenorhabditis elegans. Here we report on a systematic, genome-wide, mutagenesis screen in mice. As part of the German Human Genome Project, we have undertaken a large-scale ENU-mutagenesis screen for dominant mutations and a limited screen for recessive mutations. In screening over 14,000 mice for a large number of clinically relevant parameters, we recovered 182 mouse mutants for a variety of phenotypes. In addition, 247 variant mouse mutants are currently in genetic confirmation testing and will result in additional new mutant lines. This mutagenesis screen, along with the screen described in the accompanying paper, leads to a significant increase in the number of mouse models available to the scientific community. Our mutant lines are freely accessible to non-commercial users (for information, see http://www.gsf.de/ieg/groups/enu-mouse.html).

    Nature genetics 2000;25;4;444-7

  • Genetic control of autoimmune myocarditis mediated by myosin-specific antibodies.

    Kuan AP, Chamberlain W, Malkiel S, Lieu HD, Factor SM, Diamond B and Kotzin BL

    Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

    Autoimmune disease involves both the development of autoreactivity and the expression of organ damage, and susceptibility is genetically complex. We recently reported that in autoimmune myocarditis susceptibility to antibody-mediated cardiac injury is strain specific. DBA/2 mice develop myocarditis following administration of myosin-specific antibody, while BALB/c mice do not. This susceptibility appears to be controlled by expression of myosin in the myocardial extracellular matrix. CByD2F1 mice are both resistant to induction of myocarditis and do not demonstrate extracellular myosin, indicating a recessive genetic component to these traits. A backcross analysis of susceptibility using DBA/2xCByD2F1 mice revealed a locus on chromosome 12 that is strongly linked with myocarditis. In male mice there was a second region on chromosome 1 that also contributes to disease susceptibility. However, genetic susceptibility in both female and male mice was genetically complex. This study demonstrates that the genetic basis of tissue injury can be analyzed separately from the genetic basis of autoreactivity. Future studies will determine whether the genetic factors identified in this study are also involved in susceptibility to rheumatic fever.

    Funded by: NHLBI NIH HHS: T32HL07675; NIAMS NIH HHS: AR37070, AR43018; ...

    Immunogenetics 1999;49;2;79-85

  • Golgi vesiculation and lysosome dispersion in cells lacking cytoplasmic dynein.

    Harada A, Takei Y, Kanai Y, Tanaka Y, Nonaka S and Hirokawa N

    Department of Cell Biology and Anatomy, Graduate School of Medicine, University of Tokyo, Tokyo, 113, Japan.

    Cytoplasmic dynein, a minus end-directed, microtubule-based motor protein, is thought to drive the movement of membranous organelles and chromosomes. It is a massive complex that consists of multiple polypeptides. Among these polypeptides, the cytoplasmic dynein heavy chain (cDHC) constitutes the major part of this complex. To elucidate the function of cytoplasmic dynein, we have produced mice lacking cDHC by gene targeting. cDHC-/- embryos were indistinguishable from cDHC+/-or cDHC+/+ littermates at the blastocyst stage. However, no cDHC-/- embryos were found at 8.5 d postcoitum. When cDHC-/- blastocysts were cultured in vitro, they showed interesting phenotypes. First, the Golgi complex became highly vesiculated and distributed throughout the cytoplasm. Second, endosomes and lysosomes were not concentrated near the nucleus but were distributed evenly throughout the cytoplasm. Interestingly, the Golgi "fragments" and lysosomes were still found to be attached to microtubules. These results show that cDHC is essential for the formation and positioning of the Golgi complex. Moreover, cDHC is required for cell proliferation and proper distribution of endosomes and lysosomes. However, molecules other than cDHC might mediate attachment of the Golgi complex and endosomes/lysosomes to microtubules.

    Funded by: NICHD NIH HHS: N01-HD-2-3144

    The Journal of cell biology 1998;141;1;51-9

  • Identification of dynein heavy chain genes expressed in human and mouse testis: chromosomal localization of an axonemal dynein gene.

    Neesen J, Koehler MR, Kirschner R, Steinlein C, Kreutzberger J, Engel W and Schmid M

    Institut für Humangenetik der Universität Göttingen, Germany. jneesen@gwdg.de

    Dynein heavy chains are involved in microtubule-dependent transport processes. While cytoplasmic dyneins are involved in chromosome or vesicle movement, axonemal dyneins are essential for motility of cilia and flagella. Here we report the isolation of dynein heavy chain (DHC)-like sequences in man and mouse. Using polymerase chain reaction and reverse-transcribed human and mouse testis RNA cDNA fragments encoding the conserved ATP binding region of dynein heavy chains were amplified. We identified 11 different mouse and eight human dynein-like sequences in testis which show high similarity to known dyneins of different species such as rat, sea urchin or green algae. Sequence similarities suggest that two of the mouse clones and one human clone encode putative cytoplasmic dynein heavy chains, whereas the other sequences show higher similarity to axonemal dyneins. Two of nine axonemal dynein isoforms identified in the mouse testis are more closely related to known outer arm dyneins, while seven clones seem to belong to the inner arm dynein group. Of the isolated human isoforms three clones were classified as outer arm and four clones as inner arm dynein heavy chains. Each of the DHC cDNAs corresponds to an individual gene as determined by Southern blot experiments. The alignment of the deduced protein sequences between human (HDHC) and mouse (MDHC) dynein fragments reveals higher similarity between single human and mouse sequences than between two sequences of the same species. Human and mouse cDNA fragments were used to isolate genomic clones. Two of these clones, gHDHC7 and gMDHC7, are homologous genes encoding axonemal inner arm dyneins. While the human clone is assigned to 3p21, the mouse gene maps to chromosome 14.

    Gene 1997;200;1-2;193-202

  • Immunohistochemistry of a cytoplasmic dynein (MAP 1C)-like molecule in rodent and human brain tissue: an example of molecular mimicry between cytoplasmic dynein and influenza A virus.

    Yamada T, Yamanaka I and Nakajima S

    Department of Neurology, Chiba University, Japan.

    Immunohistochemistry with an antibody to influenza A/Aichi/2/68 (H3N2) virus was performed using normal mouse, rat and human brain tissues. Dot-like or filamentous structures in the neuronal cytoplasm were clearly stained. Axons were also stained, but weakly. Lewy bodies in Parkinson's disease substantia nigra were also positive. Immunoscreening of the antibody using mouse brain cDNA revealed that this antibody recognized the heavy chain of cytoplasmic dynein. Immunoblot analysis also showed that the reactive molecule was the same size as cytoplasmic dynein (microtubule-associated protein 1 C). This is an example of molecular mimicry between cytoplasmic dynein and influenza A virus, and the antibody appears to be useful for the localization on cytoplasmic dynein in the central nervous system.

    Acta neuropathologica 1996;92;3;306-11

  • Multiple mouse chromosomal loci for dynein-based motility.

    Vaughan KT, Mikami A, Paschal BM, Holzbaur EL, Hughes SM, Echeverri CJ, Moore KJ, Gilbert DJ, Copeland NG, Jenkins NA and Vallee RB

    Cell Biology Group, Worcester Foundation for Biomedical Research, 222 Maple Avenue, Shrewsbury, Massachusetts, 01545, USA.

    Dyneins are multisubunit mechanochemical enzymes capable of interacting with microtubules to generate force. Axonemal dyneins produce the motive force for ciliary and flagellar beating by inducing sliding between adjacent microtubules within the axoneme. Cytoplasmic dyneins translocate membranous organelles and chromosomes toward the minus ends of cytoplasmic microtubules. Dynactin is an accessory complex implicated in tethering cytoplasmic dynein to membranous organelles and mitotic kinetochores. In the studies described here, we have identified a number of new dynein genes and determined their mouse chromosomal locations by interspecific backcross analysis. We have also mapped several dynein and dynactin genes cloned previously. Our studies provide the first comprehensive attempt to map dynein and dynactin genes in mammals and provide a basis for the further analysis of dynein function in development and disease.

    Genomics 1996;36;1;29-38

  • Localization of the human cytoplasmic dynein heavy chain (DNECL) to 14qter by fluorescence in situ hybridization.

    Narayan D, Desai T, Banks A, Patanjali SR, Ravikumar TS and Ward DC

    Department of Surgery, Yale University School of Medicine, New Haven, Connecticut 06510.

    Genomics 1994;22;3;660-1

  • Molecular cloning of the retrograde transport motor cytoplasmic dynein (MAP 1C).

    Mikami A, Paschal BM, Mazumdar M and Vallee RB

    Worcester Foundation for Experimental Biology, Shrewsbury, Massachusetts 01545.

    Overlapping cDNAs encoding the entire heavy chain of cytoplasmic dynein (MAP 1C) have been obtained. A 4644 amino acid polypeptide containing four ATP-binding consensus sequences is predicted. Homology with the sea urchin flagellar outer arm dynein beta heavy chain is observed within the C-terminal two-thirds of the protein. The N-terminal third of the two polypeptides shows no clear relationship, suggesting that this region of MAP 1C is responsible for its association with retrograde organelles and other functions. Northern blot analysis reveals a 16.5 kb band in brain and other tissues. Southern blot analysis is consistent with a single cytoplasmic dynein gene. Thus, in contrast with cilia and flagella, which contain numerous forms of dynein, our results are consistent with the existence of only a single cytoplasmic dynein heavy chain gene, which appears to produce only a single transcript.

    Funded by: NIGMS NIH HHS: GM 26701, GM 47434

    Neuron 1993;10;5;787-96

  • End-plates, transmission and contractile characteristics of muscles without spindles in the hereditary sensory neuropathy of the Sprawling mouse.

    Brook GA and Duchen LW

    Department of Neuropathology, National Hospitals for Nervous Diseases, London, UK.

    In the mutant mouse Sprawling, a deficiency of sensory ganglion cells is associated with a failure of the development of spindles and tendon organs particularly affecting muscles of the hindleg. Electrophysiological and morphological investigations were made on nerve, muscle and the neuromuscular junction of soleus and extensor digitorum longus (EDL). It was found that the absence of sensory innervation had no effect on the development of muscle bulk, on the fibre diameters or on histochemical profiles. The elimination of polyneuronal innervation proceeded at the normal rate and was complete by 3 wks of age. The strength of contractile responses and the number of motor units were normal in both muscles. End-plate areas were measured and the size distribution found to be normal in soleus. In EDL, however, there was a preponderance of small end-plates and a relative deficiency of large ones. This was associated with an abnormally low frequency of miniature end-plate potentials and of the mean quantal content of transmission. There was also a reduction in the complexity of the postsynaptic specialization at end-plates in the EDL. Localized axonal swellings packed with neurofilaments were observed in preterminal motor nerve fibres, which suggested an abnormality of axonal transport. There was no evidence of denervation of muscle fibres. The contractile characteristics of soleus and EDL were still distinguishable as slow and fast-twitch, respectively, despite the abnormalities found, and it seems likely that impulse traffic in the lower motoneuron is only marginally affected, if at all. An abnormality of axonal transport may be responsible for the inability of motoneurons to maintain large end-plates in fast-twitch muscles.

    Brain : a journal of neurology 1990;113 ( Pt 4);867-91

  • The development of sensory ganglion cells in normal and Sprawling mutant mice.

    Scaravilli F and Duchen LW

    The foetal and early post-natal development of dorsal root ganglion cells in normal and Sprawling (Swl) mutant mice was studied by light and electron microscopy. As early as the 11th foetal day the nucleus of some neurons showed an indentation of its membrane and by the 13th day this abnormality was marked and present in many ganglion cells of foetuses which were, therefore, identified as presumptive Swl'. A peripherally situated nucleus and the aggregation of filaments and organelles in the central perikaryon were also early abnormalities, similar to those of the sensory neurons of the adult Swl mouse. In the normal ganglion cells, nuclei were rounded and central by the 16th foetal day and nuclear indentations were never seen, thus making a clear distinction possible between normal and Swl foetuses.

    Journal of neurocytology 1980;9;3;363-71

  • Electron microscopic and quantitative studies of cell necrosis in developing sensory ganglia in normal and Sprawling mutant mice.

    Scaravilli F and Duchen LW

    The percentage of neurons undergoing necrosis during foetal and early post-natal development in normal and Sprawling (Swl) mutant mice was determined. Two major peaks in the occurrence of necrosis were found at the 13th and the 19th foetal days in both groups of mice but at all stages the incidence was greater in Swl. Electron microscopically the first degenerative changes seemed to involve the perikaryon while many of the cells undergoing necrosis in Swl already showed the characteristic abnormalities previously described in that mutant.

    Journal of neurocytology 1980;9;3;373-80

  • Quantitative and electron microscopic studies of sensory ganglion cells of the Sprawling mouse.

    Duchen LW and Scaravilli F

    The L4-6 sensory root ganglia of young and adult Sprawling (Swl) and normal mice were studied. Cell counts showed a great reduction in the total number of ganglion cells in Swl. Cell degeneration was observed in young Swl animals but not in normal littermates. Most of the remaining ganglion cells showed morphological abnormalities very similar to those seen in chromatolytic neurons-enlarged nucleolus, eccentric nucleus with an infolded nuclear membrane, loss of juxtanuclear Nissl bodies and an increase in neurofilaments, Golgi membranes, autophagic vacuoles, and dense bodies. In contrast to the classical changes of chromatolysis the abnormalities in Swl neurons persisted throughout the lifespan of the animals. Reconstructions from serial sections showed that ganglion cells in Swl were highly irregular in shape.

    Journal of neurocytology 1977;6;4;465-81

  • The structure and composition of peripheral nerves and nerve roots in the Sprawling mouse.

    Duchen LW and Scaravilli F

    Peripheral nerves and lumbar nerve roots of Sprawling, a neurological mutant mouse, were examined with light and electron microscopy. The peripheral nerves and the dorsal roots were thin and grey and were composed predominantly of small myelinated and unmyelinated axons. No evidence of axonal or myelin degeneration was found. Quantitative studies showed a marked reduction in the total number of myelinated axons with preponderance of those of 2-5 micron in diameter or less, most marked in the dorsal roots in which there was also an increase in the proportion of axons which were unmyelinated. In the ventral roots there was a deficiency in the contribution formed by myelinated axons of small calibre, probably indicating a deficiency of gamma fibres. Examination of the myelinated axons in nerves and roots showed a normal relationship between fibre size and internodal lengths and number of myelin lamellae. The findings suggest that the genetic defect in Sprawling is responsible for a failure of myelination of sensory axons. The deficiency of large sensory axons and of small motor axons can be correlated with the deficiency of muscle spindles.

    Journal of anatomy 1977;123;Pt 3;763-75

  • A dominant hereditary sensory disorder in the mouse with deficiency of muscle spindles: the mutant Sprawling.

    Duchen LW

    The Journal of physiology 1974;237;2;10P-11P

Gene lists (6)

Gene List Source Species Name Description Gene count
L00000001 G2C Mus musculus Mouse PSD Mouse PSD adapted from Collins et al (2006) 1080
L00000008 G2C Mus musculus Mouse PSP Mouse PSP adapted from Collins et al (2006) 1121
L00000060 G2C Mus musculus BAYES-COLLINS-HUMAN-PSD-CONSENSUS Human cortex PSD consensus (ortho) 748
L00000062 G2C Mus musculus BAYES-COLLINS-MOUSE-PSD-CONSENSUS Mouse cortex PSD consensus 984
L00000070 G2C Mus musculus BAYES-COLLINS-HUMAN-PSD-FULL Human cortex biopsy PSD full list (ortho) 1461
L00000072 G2C Mus musculus BAYES-COLLINS-MOUSE-PSD-FULL Mouse cortex PSD full list 1556
© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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