G2Cdb::Gene report

Gene id
Gene symbol
Dctn1 (MGI)
Mus musculus
dynactin 1
G00002012 (Homo sapiens)

Databases (8)

ENSMUSG00000031865 (Ensembl mouse gene)
13191 (Entrez Gene)
1200 (G2Cdb plasticity & disease)
Gene Expression
NM_007835 (Allen Brain Atlas)
13191 (Genepaint)
601143 (OMIM)
Marker Symbol
MGI:107745 (MGI)
Protein Sequence
O08788 (UniProt)

Synonyms (3)

  • Glued
  • p150
  • p150<glued>

Literature (26)

Pubmed - other

  • KASH protein Syne-2/Nesprin-2 and SUN proteins SUN1/2 mediate nuclear migration during mammalian retinal development.

    Yu J, Lei K, Zhou M, Craft CM, Xu G, Xu T, Zhuang Y, Xu R and Han M

    Institute of Developmental Biology and Molecular Medicine, School of Life Science, Fudan University, Shanghai 200433, China.

    Nuclear movement relative to cell bodies is a fundamental process during certain aspects of mammalian retinal development. During the generation of photoreceptor cells in the cell division cycle, the nuclei of progenitors oscillate between the apical and basal surfaces of the neuroblastic layer (NBL). This process is termed interkinetic nuclear migration (INM). Furthermore, newly formed photoreceptor cells migrate and form the outer nuclear layer (ONL). In the current study, we demonstrated that a KASH domain-containing protein, Syne-2/Nesprin-2, as well as SUN domain-containing proteins, SUN1 and SUN2, play critical roles during INM and photoreceptor cell migration in the mouse retina. A deletion mutation of Syne-2/Nesprin-2 or double mutations of Sun1 and Sun2 caused severe reduction of the thickness of the ONL, mislocalization of photoreceptor nuclei and profound electrophysiological dysfunction of the retina characterized by a reduction of a- and b-wave amplitudes. We also provide evidence that Syne-2/Nesprin-2 forms complexes with either SUN1 or SUN2 at the nuclear envelope to connect the nucleus with dynein/dynactin and kinesin molecular motors during the nuclear migrations in the retina. These key retinal developmental signaling results will advance our understanding of the mechanism of nuclear migration in the mammalian retina.

    Funded by: NEI NIH HHS: EY015851, EY03040

    Human molecular genetics 2011;20;6;1061-73

  • Pericentrosomal targeting of Rab6 secretory vesicles by Bicaudal-D-related protein 1 (BICDR-1) regulates neuritogenesis.

    Schlager MA, Kapitein LC, Grigoriev I, Burzynski GM, Wulf PS, Keijzer N, de Graaff E, Fukuda M, Shepherd IT, Akhmanova A and Hoogenraad CC

    Department of Neuroscience, Erasmus Medical Center, Rotterdam, The Netherlands.

    Membrane and secretory trafficking are essential for proper neuronal development. However, the molecular mechanisms that organize secretory trafficking are poorly understood. Here, we identify Bicaudal-D-related protein 1 (BICDR-1) as an effector of the small GTPase Rab6 and key component of the molecular machinery that controls secretory vesicle transport in developing neurons. BICDR-1 interacts with kinesin motor Kif1C, the dynein/dynactin retrograde motor complex, regulates the pericentrosomal localization of Rab6-positive secretory vesicles and is required for neural development in zebrafish. BICDR-1 expression is high during early neuronal development and strongly declines during neurite outgrowth. In young neurons, BICDR-1 accumulates Rab6 secretory vesicles around the centrosome, restricts anterograde secretory transport and inhibits neuritogenesis. Later during development, BICDR-1 expression is strongly reduced, which permits anterograde secretory transport required for neurite outgrowth. These results indicate an important role for BICDR-1 as temporal regulator of secretory trafficking during the early phase of neuronal differentiation.

    The EMBO journal 2010;29;10;1637-51

  • mNUDC is required for plus-end-directed transport of cytoplasmic dynein and dynactins by kinesin-1.

    Yamada M, Toba S, Takitoh T, Yoshida Y, Mori D, Nakamura T, Iwane AH, Yanagida T, Imai H, Yu-Lee LY, Schroer T, Wynshaw-Boris A and Hirotsune S

    Department of Genetic Disease Research, Graduate School of Medicine, Osaka City University, Osaka, Japan.

    Lissencephaly is a devastating neurological disorder caused by defective neuronal migration. The LIS1 (or PAFAH1B1) gene was identified as the gene mutated in lissencephaly patients, and was found to regulate cytoplasmic dynein function and localization. In particular, LIS1 is essential for anterograde transport of cytoplasmic dynein as a part of the cytoplasmic dynein-LIS1-microtubule complex in a kinesin-1-dependent manner. However, the underlying mechanism by which a cytoplasmic dynein-LIS1-microtubule complex binds kinesin-1 is unknown. Here, we report that mNUDC (mammalian NUDC) interacts with kinesin-1 and is required for the anterograde transport of a cytoplasmic dynein complex by kinesin-1. mNUDC is also required for anterograde transport of a dynactin-containing complex. Inhibition of mNUDC severely suppressed anterograde transport of distinct cytoplasmic dynein and dynactin complexes, whereas motility of kinesin-1 remained intact. Reconstruction experiments clearly demonstrated that mNUDC mediates the interaction of the dynein or dynactin complex with kinesin-1 and supports their transport by kinesin-1. Our findings have uncovered an essential role of mNUDC for anterograde transport of dynein and dynactin by kinesin-1.

    Funded by: NICHD NIH HHS: HD47380, R01 HD047380; NINDS NIH HHS: NS41030, R01 NS041030

    The EMBO journal 2010;29;3;517-31

  • SUN1/2 and Syne/Nesprin-1/2 complexes connect centrosome to the nucleus during neurogenesis and neuronal migration in mice.

    Zhang X, Lei K, Yuan X, Wu X, Zhuang Y, Xu T, Xu R and Han M

    Institute of Developmental Biology and Molecular Medicine, School of Life Science, Fudan University, Shanghai, China.

    Nuclear movement is critical during neurogenesis and neuronal migration, which are fundamental for mammalian brain development. Although dynein, Lis1, and other cytoplasmic proteins are known for their roles in connecting microtubules to the nucleus during interkinetic nuclear migration (INM) and nucleokinesis, the factors connecting dynein/Lis1 to the nuclear envelope (NE) remain to be determined. We report here that the SUN-domain proteins SUN1 and SUN2 and the KASH-domain proteins Syne-1/Nesprin-1 and Syne-2/Nesprin-2 play critical roles in neurogenesis and neuronal migration in mice. We show that SUN1 and SUN2 redundantly form complexes with Syne-2 to mediate the centrosome-nucleus coupling during both INM and radial neuronal migration in the cerebral cortex. Syne-2 is connected to the centrosome through interactions with both dynein/dynactin and kinesin complexes. Syne-2 mutants also display severe defects in learning and memory. These results fill an important gap in our understanding of the mechanism of nuclear movement during brain development.

    Funded by: Howard Hughes Medical Institute

    Neuron 2009;64;2;173-87

  • Alpha-E-catenin binds to dynamitin and regulates dynactin-mediated intracellular traffic.

    Lien WH, Gelfand VI and Vasioukhin V

    Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.

    Alpha-epithelial catenin (E-catenin) is an important cell-cell adhesion protein. In this study, we show that alpha-E-catenin also regulates intracellular traffic by binding to the dynactin complex component dynamitin. Dynactin-mediated organelle trafficking is increased in alpha-E-catenin(-/-) keratinocytes, an effect that is reversed by expression of exogenous alpha-E-catenin. Disruption of adherens junctions in low-calcium media does not affect dynactin-mediated traffic, indicating that alpha-E-catenin regulates traffic independently from its function in cell-cell adhesion. Although neither the integrity of dynactin-dynein complexes nor their association with vesicles is affected by alpha-E-catenin, alpha-E-catenin is necessary for the attenuation of microtubule-dependent trafficking by the actin cytoskeleton. Because the actin-binding domain of alpha-E-catenin is necessary for this regulation, we hypothesize that alpha-E-catenin functions as a dynamic link between the dynactin complex and actin and, thus, integrates the microtubule and actin cytoskeleton during intracellular trafficking.

    Funded by: NCI NIH HHS: CA098161, R01 CA098161; NIGMS NIH HHS: GM-52111, R01 GM052111

    The Journal of cell biology 2008;183;6;989-97

  • 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

  • Dynactin is essential for growth cone advance.

    Abe TK, Honda T, Takei K, Mikoshiba K, Hoffman-Kim D, Jay DG and Kuwano R

    Center of Bioresource-based Researches, Brain Research Institute, Niigata University, 1 Asahimachi, Chuo-ku, Niigata 951-8585, Japan.

    Dynactin is a multi-subunit complex that serves as a critical cofactor of the microtubule motor cytoplasmic dynein. We previously identified dynactin in the nerve growth cone. However, the function of dynactin in the growth cone is still unclear. Here we show that dynactin in the growth cone is required for constant forward movement of the growth cone. Chromophore-assisted laser inactivation (CALI) of dynamitin, a dynactin subunit, within the growth cone markedly decreases the rate of growth cone advance. CALI of dynamitin in vitro dissociates another dynactin subunit, p150(Glued), from dynamitin. These results indicate that dynactin, especially the interaction between dynamitin and p150(Glued), plays an essential role in growth cone advance.

    Funded by: NCI NIH HHS: R01 CA116642

    Biochemical and biophysical research communications 2008;372;3;418-22

  • Nudel binds Cdc42GAP to modulate Cdc42 activity at the leading edge of migrating cells.

    Shen Y, Li N, Wu S, Zhou Y, Shan Y, Zhang Q, Ding C, Yuan Q, Zhao F, Zeng R and Zhu X

    Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China.

    Cdc42GAP promotes inactivation of Cdc42, a small GTPase whose activation at the leading edge by guanine nucleotide exchange factors is critical for cell migration. How Cdc42GAP is regulated to ensure proper levels of active Cdc42 is poorly understood. Here we show that Nudel, a cytoplasmic dynein regulator, competes with Cdc42 for binding Cdc42GAP. Consequently, Nudel can inhibit Cdc42GAP-mediated inactivation of Cdc42 in a dose-dependent manner. Both Nudel and Cdc42GAP exhibit leading-edge localization in migrating cells. The localization of Nudel requires its phosphorylation by Erk1/2. Depleting Nudel by RNAi or overexpression of a nonphosphorylatable mutant abolishes Cdc42 activation and cell migration. Our data thus uncover Nudel as a regulator of Cdc42 during cell migration. Nudel facilitates cell migration by sequestering Cdc42GAP at the leading edge to stabilize active Cdc42 in response to extracellular stimuli. Excess active Cdc42 may in turn control its own activity by recruiting Cdc42GAP from Nudel.

    Developmental cell 2008;14;3;342-53

  • The G59S mutation in p150(glued) causes dysfunction of dynactin in mice.

    Lai C, Lin X, Chandran J, Shim H, Yang WJ and Cai H

    Unit of Transgenesis, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA.

    The G59S missense mutation at the conserved microtubule-binding domain of p150(glued), a major component of dynein/dynactin complex, has been linked to an autosomal dominant form of motor neuron disease (MND). To study how this mutation affects the function of the dynein/dynactin complex and contributes to motor neuron degeneration, we generated p150(glued) G59S knock-in mice. We found that the G59S mutation destabilizes p150(glued) and disrupts the function of dynein/dynactin complex, resulting in early embryonic lethality of homozygous knock-in mice. Heterozygous knock-in mice, which developed normally, displayed MND-like phenotypes after 10 months of age, including excessive accumulation of cytoskeletal and synaptic vesicle proteins at neuromuscular junctions, loss of spinal motor neurons, increase of reactive astrogliosis, and shortening of gait compared with wild-type littermates and age-matched p150(glued) heterozygous knock-out mice. Our findings indicate that the G59S mutation in p150(glued) abrogates the normal function of p150(glued) and accelerates motor neuron degeneration.

    Funded by: Intramural NIH HHS: Z01 AG000959-04, Z99 AG999999

    The Journal of neuroscience : the official journal of the Society for Neuroscience 2007;27;51;13982-90

  • Interaction of tau protein with the dynactin complex.

    Magnani E, Fan J, Gasparini L, Golding M, Williams M, Schiavo G, Goedert M, Amos LA and Spillantini MG

    Department of Clinical Neurosciences, Brain Repair Centre, University of Cambridge, Cambridge, UK.

    Tau is an axonal microtubule-associated protein involved in microtubule assembly and stabilization. Mutations in Tau cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), and tau aggregates are present in Alzheimer's disease and other tauopathies. The mechanisms leading from tau dysfunction to neurodegeneration are still debated. The dynein-activator complex dynactin has an essential role in axonal transport and mutations in its gene are associated with lower motor neuron disease. We show here for the first time that the N-terminal projection domain of tau binds to the C-terminus of the p150 subunit of the dynactin complex. Tau and dynactin show extensive colocalization, and the attachment of the dynactin complex to microtubules is enhanced by tau. Mutations of a conserved arginine residue in the N-terminus of tau, found in patients with FTDP-17, affect its binding to dynactin, which is abnormally distributed in the retinal ganglion cell axons of transgenic mice expressing human tau with a mutation in the microtubule-binding domain. These findings, which suggest a direct involvement of tau in axonal transport, have implications for understanding the pathogenesis of tauopathies.

    Funded by: Medical Research Council: G0301152, MC_U105184291, MC_U105184313, U.1051.04.002(78842)

    The EMBO journal 2007;26;21;4546-54

  • Retrolinkin, a membrane protein, plays an important role in retrograde axonal transport.

    Liu JJ, Ding J, Wu C, Bhagavatula P, Cui B, Chu S, Mobley WC and Yang Y

    Department of Neurology, Stanford University School of Medicine, Stanford, CA 94305, USA.

    Retrograde axonal transport plays an important role in the maintenance of neuronal functions, but the mechanism is poorly defined partly because the constituents of the retrograde transport system and their interactions have yet to be elucidated. Of special interest is how dynein/dynactin motor proteins interact with membrane cargoes. Here, we report that an endosomal vesicle protein, termed retrolinkin, functions as a receptor tethering vesicles to dynein/dynactin through BPAG1n4. Retrolinkin, a membrane protein highly enriched in neuronal endosomes, binds directly to BPAG1n4. Deletion of retrolinkin membrane-association domains disrupts retrograde vesicular transport, recapitulating the BPAG1 null phenotype. We propose that retrolinkin acts with BPAG1n4 to specifically regulate retrograde axonal transport. Our work lays the foundation for understanding fundamental issues of axonal transport and provides insights into the molecular mechanisms underlying human neurodegenerative disorders.

    Funded by: NINDS NIH HHS: K02 NS043281, NS24054, NS42791, NS43281, R01 NS024054, R01 NS042791

    Proceedings of the National Academy of Sciences of the United States of America 2007;104;7;2223-8

  • Axonal dynactin p150Glued transports caspase-8 to drive retrograde olfactory receptor neuron apoptosis.

    Carson C, Saleh M, Fung FW, Nicholson DW and Roskams AJ

    Department of Zoology, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4.

    Olfactory receptor neurons (ORNs) undergo caspase-mediated retrograde apoptosis after target removal (bulbectomy), in which axonal caspase-9 and caspase-3 activation leads to terminal apoptosis in ORN soma of the olfactory epithelium. Here, we show that caspase-8 can act as an initiator of ORN apoptosis after bulbectomy and also after synaptic instability is induced by NMDA-mediated excitotoxic death of ORN target neurons in the olfactory bulb. Caspase-8 and caspase-3 are sequentially activated within ORN presynaptic terminals, and caspase-8 complexes with dynactin p150Glued, (a retrograde motor protein) and is transported retrogradely, preceding axonal caspase-3 activation and apoptosis of ORN cell bodies. Focal in vivo inhibition of initiator caspase activation or microtubule-dependent transport (with Taxol) at the lesioned axon terminus results in a significant reduction in retrograde axonal caspase-8 and caspase-3 activation and inhibition of retrograde ORN death. Caspase-8 activation and retrograde transport after NMDA lesion is similarly reduced in mice null for p75, the low-affinity nerve growth factor receptor. The retrograde apoptosis of ORNs thus involves a novel mechanism that used p75 in the local activation of caspase-8. Once caspase-8 is maximally activated in the presynaptic terminal, it is transported retrogradely by the motor complex dynactin/dynein, a process that can be inhibited focally to inhibit ORN apoptosis after acute axonal lesion. These data have revealed a novel mechanism of retrograde apoptosis, in which caspase-8 complexes directly with axonal dynactin p150Glued to reveal a differential vulnerability of subpopulations of ORNs to undergo apoptosis after axonal damage and the loss of olfactory bulb target neurons.

    Funded by: NIDCD NIH HHS: 5 R01 DC04579-04

    The Journal of neuroscience : the official journal of the Society for Neuroscience 2005;25;26;6092-104

  • Libraries enriched for alternatively spliced exons reveal splicing patterns in melanocytes and melanomas.

    Watahiki A, Waki K, Hayatsu N, Shiraki T, Kondo S, Nakamura M, Sasaki D, Arakawa T, Kawai J, Harbers M, Hayashizaki Y and Carninci P

    Genome Science Laboratory, RIKEN, Wako main campus, 2-1 Hirosawa, Wako, Saitama, 351-0198 Japan.

    It is becoming increasingly clear that alternative splicing enables the complex development and homeostasis of higher organisms. To gain a better understanding of how splicing contributes to regulatory pathways, we have developed an alternative splicing library approach for the identification of alternatively spliced exons and their flanking regions by alternative splicing sequence enriched tags sequencing. Here, we have applied our approach to mouse melan-c melanocyte and B16-F10Y melanoma cell lines, in which 5,401 genes were found to be alternatively spliced. These genes include those encoding important regulatory factors such as cyclin D2, Ilk, MAPK12, MAPK14, RAB4, melastatin 1 and previously unidentified splicing events for 436 genes. Real-time PCR further identified cell line-specific exons for Tmc6, Abi1, Sorbs1, Ndel1 and Snx16. Thus, the ASL approach proved effective in identifying splicing events, which suggest that alternative splicing is important in melanoma development.

    Nature methods 2004;1;3;233-9

  • EB1 and APC bind to mDia to stabilize microtubules downstream of Rho and promote cell migration.

    Wen Y, Eng CH, Schmoranzer J, Cabrera-Poch N, Morris EJ, Chen M, Wallar BJ, Alberts AS and Gundersen GG

    Department of Anatomy & Cell Biology, Columbia University, New York, NY 10032, USA.

    Lysophosphatidic acid (LPA) stimulates Rho GTPase and its effector, the formin mDia, to capture and stabilize microtubules in fibroblasts. We investigated whether mammalian EB1 and adenomatous polyposis coli (APC) function downstream of Rho-mDia in microtubule stabilization. A carboxy-terminal APC-binding fragment of EB1 (EB1-C) functioned as a dominant-negative inhibitor of microtubule stabilization induced by LPA or active mDia. Knockdown of EB1 with small interfering RNAs also prevented microtubule stabilization. Expression of either full-length EB1 or APC, but not an APC-binding mutant of EB1, was sufficient to stabilize microtubules. Binding and localization studies showed that EB1, APC and mDia may form a complex at stable microtubule ends. Furthermore, EB1-C, but not an APC-binding mutant, inhibited fibroblast migration in an in vitro wounding assay. These results show an evolutionarily conserved pathway for microtubule capture, and suggest that mDia functions as a scaffold protein for EB1 and APC to stabilize microtubules and promote cell migration.

    Funded by: NIGMS NIH HHS: GM62939

    Nature cell biology 2004;6;9;820-30

  • Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules.

    Gauthier LR, Charrin BC, Borrell-Pagès M, Dompierre JP, Rangone H, Cordelières FP, De Mey J, MacDonald ME, Lessmann V, Humbert S and Saudou F

    Unité Mixte de Recherche 146, Centre National de la Recherche Scientifique, Institut Curie, Building 110, Centre Universitaire, 91405 Orsay Cedex, France.

    Polyglutamine expansion (polyQ) in the protein huntingtin is pathogenic and responsible for the neuronal toxicity associated with Huntington's disease (HD). Although wild-type huntingtin possesses antiapoptotic properties, the relationship between the neuroprotective functions of huntingtin and pathogenesis of HD remains unclear. Here, we show that huntingtin specifically enhances vesicular transport of brain-derived neurotrophic factor (BDNF) along microtubules. Huntingtin-mediated transport involves huntingtin-associated protein-1 (HAP1) and the p150(Glued) subunit of dynactin, an essential component of molecular motors. BDNF transport is attenuated both in the disease context and by reducing the levels of wild-type huntingtin. The alteration of the huntingtin/HAP1/p150(Glued) complex correlates with reduced association of motor proteins with microtubules. Finally, we find that the polyQ-huntingtin-induced transport deficit results in the loss of neurotrophic support and neuronal toxicity. Our findings indicate that a key role of huntingtin is to promote BDNF transport and suggest that loss of this function might contribute to pathogenesis.

    Funded by: NIMH NIH HHS: MH/NS 31862

    Cell 2004;118;1;127-38

  • 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

  • BPAG1n4 is essential for retrograde axonal transport in sensory neurons.

    Liu JJ, Ding J, Kowal AS, Nardine T, Allen E, Delcroix JD, Wu C, Mobley W, Fuchs E and Yang Y

    Department of Neurology, Stanford University School of Medicine, Stanford, CA 94305-5489, USA. yanmin.yang@stanford.edu

    Disruption of the BPAG1 (bullous pemphigoid antigen 1) gene results in progressive deterioration in motor function and devastating sensory neurodegeneration in the null mice. We have previously demonstrated that BPAG1n1 and BPAG1n3 play important roles in organizing cytoskeletal networks in vivo. Here, we characterize functions of a novel BPAG1 neuronal isoform, BPAG1n4. Results obtained from yeast two-hybrid screening, blot overlay binding assays, and coimmunoprecipitations demonstrate that BPAG1n4 interacts directly with dynactin p150Glued through its unique ezrin/radixin/moesin domain. Studies using double immunofluorescent microscopy and ultrastructural analysis reveal physiological colocalization of BPAG1n4 with dynactin/dynein. Disruption of the interaction between BPAG1n4 and dynactin results in severe defects in retrograde axonal transport. We conclude that BPAG1n4 plays an essential role in retrograde axonal transport in sensory neurons. These findings might advance our understanding of pathogenesis of axonal degeneration and neuronal death.

    Funded by: NIA NIH HHS: AG16999, R01 AG016999; NIAMS NIH HHS: AR27883, R01 AR027883, R37 AR027883; NINDS NIH HHS: K02 NS043281, NS24054, NS38869, NS42791, NS43281, R01 NS024054, R01 NS038869, R01 NS042791

    The Journal of cell biology 2003;163;2;223-9

  • 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

  • Targeted disruption of Huntingtin-associated protein-1 (Hap1) results in postnatal death due to depressed feeding behavior.

    Chan EY, Nasir J, Gutekunst CA, Coleman S, Maclean A, Maas A, Metzler M, Gertsenstein M, Ross CA, Nagy A and Hayden MR

    Center for Molecular Medicine and Therapeutics, Department of Medical Genetics, Children's and Women's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.

    HAP-1 is a huntingtin-associated protein that is enriched in the brain. To gain insight into the normal physiological role of HAP-1, mice were generated with homozygous disruption at the Hap1 locus. Loss of HAP-1 expression did not alter the gross brain expression levels of its interacting partners, huntingtin and p150glued. Newborn Hap1(-/-) animals are observed at the expected Mendelian frequency suggesting a non-essential role of HAP-1 during embryogenesis. Postnatally, Hap1(-/-) pups show decreased feeding behavior that ultimately leads to malnutrition, dehydration and premature death. Seventy percent of Hap1(-/-) pups fail to survive past the second postnatal day (P2) and 100% of Hap1(-/-) pups fail to survive past P9. From P2 until death, Hap1(-/-) pups show markedly decreased amounts of ingested milk. Hap1(-/-) pups that survive to P8 show signs of starvation including greatly decreased serum leptin levels, decreased brain weight and atrophy of the brain cortical mantel. HAP-1 is particularly enriched in the hypothalamus, which is well documented to regulate feeding behavior. Our results demonstrate that HAP-1 plays an essential role in regulating postnatal feeding.

    Human molecular genetics 2002;11;8;945-59

  • Construction of long-transcript enriched cDNA libraries from submicrogram amounts of total RNAs by a universal PCR amplification method.

    Piao Y, Ko NT, Lim MK and Ko MS

    Developmental Genomics and Aging Section, Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.

    Here we report a novel design of linker primer that allows one to differentially amplify long tracts (average 3.0 kb with size ranges of 1-7 kb) or short DNAs (average 1.5 kb with size ranges of 0.5-3 kb) from a complex mixture. The method allows one to generate cDNA libraries enriched for long transcripts without size selection of insert DNAs. One representative library from newborn kidney includes 70% of clones bearing ATG start codons. A comparable library has been generated from 20 mouse blastocysts, containing only approximately 40 ng of total RNA. This universal PCR amplification scheme can provide a route to isolate very large cDNAs, even if they are expressed at very low levels.

    Genome research 2001;11;9;1553-8

  • 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

  • High-resolution genetic, physical, and transcript map of the mnd2 region of mouse chromosome 6.

    Weber JS, Jang W, Simin K, Lu W, Yu J and Meisler MH

    Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, 48109-0618, USA.

    The autosomal recessive mutation mnd2 is responsible for a lethal neuromuscular wasting disorder in the mouse. A high-resolution genetic map of the mnd2 region of mouse chromosome 6 was generated by analysis of 1147 F2 offspring from an intersubspecific cross between strains C57BL/6J-mnd2/+ and CAST/Ei. The results localize mnd2 to the 0.2-cM interval between D6Mit164 and D6Mit128. A contig of overlapping YAC, BAC, and P1 clones spanning the nonrecombinant interval was constructed. One novel gene isolated from the contig, D6Mm3e, is a new member of the WD repeat gene family. The observed gene order for the five positional candidate genes previously mapped to the region and five newly isolated genes is centromere-Hexokinase II-D6Mm5e-p62 Dok-Aup1-Rhotekin, D6Mm3e-Dynactin 1-Smooth muscle gamma actin-D6Mm4e-beta-adducin-telomere. Seven of these genes are located within the 400-kb nonrecombinant interval for mnd2. Comparison between wildtype and mutant failed to detect any differences in mRNA size, abundance, or coding sequence for these seven genes. The genes described here are positional candidates for the Parkinson disease susceptibility locus PARK3 that was recently mapped to the corresponding region of human chromosome band 2p13.1.

    Genomics 1998;54;1;107-15

  • The presence of the 50-kDa subunit of dynactin complex in the nerve growth cone.

    Abe TK, Tanaka H, Iwanaga T, Odani S and Kuwano R

    Research Laboratory for Molecular Genetics, Niigata University, Asahimachi, Japan.

    Membrane proteins in growth cone-enriched and growth cone-non-enriched fractions prepared from neonatal mouse brain were separated by lectin-affinity and ion exchange chromatographies, 2D-PAGE, and SDS-PAGE. Partial amino acid sequences of the proteins concentrated in the growth cone-enriched fraction were determined. We found that one such protein, gmp23-48k, corresponds to the 50-kDa subunit (p50) of the dynactin complex. An antibody raised against gmp23-48k strongly reacted with growth cones of differentiated neuronal precursor cells. Immunoblot analyses revealed that gmp23-48k was present both in membrane and in soluble fractions of neonatal brain. However, the amount of gmp23-48k in the membrane fraction greatly decreased in adult brain. These results suggest a special role of membrane-associated gmp23-48k/p50 in synapse formation during brain development.

    Biochemical and biophysical research communications 1997;233;2;295-9

  • Mouse p150Glued (dynactin 1) cDNA sequence and evaluation as a candidate for the neuromuscular disease mutation mnd2.

    Jang W, Weber JS, Tokito MK, Holzbaur EL and Meisler MH

    Department of Human Genetics, University of Michigan Medical School, Ann Arbor 48108-0618, USA.

    p150Glued (Dynactin 1) is a component of the dynactin complex that is essential for retrograde axonal transport in neurons. The mouse p150Glued cDNA was isolated from mouse brain by RT-PCR. The complete sequence of the full length mouse cDNA was determined, including 19 bp of 5' UTR, 3843 bp of coding sequence, and 162 bp of 3' UTR. The predicted protein has a molecular mass of 142 kDa and exhibits 95% amino acid sequence identity to the predicted amino acid sequence of human p150Glued (DCTN1). The mouse Dctn1 gene was previously mapped in the central region of mouse chromosome 6, close to the neuromuscular disease gene mnd2. Northern blot analysis, complete sequencing of the cDNA, Western blot, and functional tests of the protein did not detect any abnormalities of p150Glued in mnd2 mice.

    Funded by: NIGMS NIH HHS: GM24872, GM48661

    Biochemical and biophysical research communications 1997;231;2;344-7

  • 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

  • Isolation of novel tissue-specific genes from cDNA libraries representing the individual tissue constituents of the gastrulating mouse embryo.

    Harrison SM, Dunwoodie SL, Arkell RM, Lehrach H and Beddington RS

    National Institute for Medical Research, London, UK.

    A total of 5 conventional, directionally cloned plasmid cDNA libraries have been constructed from the entire embryonic region of the mid-gastrulation mouse embryo and from its four principal tissue constituents (ectoderm, mesoderm, endoderm and primitive streak). These libraries have been validated with respect to the number of independent clones, insert-size and appropriate representation of diagnostic marker genes. Subtractive hybridisation has been used to remove clones common to the Endoderm and Mesoderm cDNA libraries resulting in an Endoderm minus Mesoderm subtracted library. Probe prepared from this subtracted library has been hybridised to a grid containing approximately 18,500 Embryonic Region library clones. Three novel clones have been recovered as well as expected genes already known to be highly expressed in the primitive endoderm lineage at this stage of development. In situ hybridisation to early postimplantation embryos has revealed the expression patterns of these novel genes. One is highly expressed exclusively in visceral endoderm, one is expressed in ectodermal and endodermal tissues, and the third proves to be an early marker of prospective and differentiated surface ectoderm as well as being expressed in endoderm and its derivatives.

    Development (Cambridge, England) 1995;121;8;2479-89

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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