G2Cdb::Gene report

Gene id
Gene symbol
Fgd4 (MGI)
Mus musculus
FYVE, RhoGEF and PH domain containing 4
G00002396 (Homo sapiens)

Databases (9)

ENSMUSG00000022788 (Ensembl mouse gene)
224014 (Entrez Gene)
154 (G2Cdb plasticity & disease)
Gene Expression
NM_139232 (Allen Brain Atlas)
g01973 (BGEM)
224014 (Genepaint)
fgd4 (gensat)
Marker Symbol
MGI:2183747 (MGI)
Protein Sequence
Q91ZT5 (UniProt)

Synonyms (5)

  • Frabin
  • Frabin-alpha
  • Frabin-beta
  • Frabin-gamma
  • ZFYVE6

Literature (14)

Pubmed - other

  • 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

  • Identification of transcripts with enriched expression in the developing and adult pancreas.

    Hoffman BG, Zavaglia B, Witzsche J, Ruiz de Algara T, Beach M, Hoodless PA, Jones SJ, Marra MA and Helgason CD

    Department of Cancer Endocrinology, BC Cancer Research Center, West 10th Ave, Vancouver, BC V5Z 1L3, Canada. bhoffman@bccrc.ca

    Background: Despite recent advances, the transcriptional hierarchy driving pancreas organogenesis remains largely unknown, in part due to the paucity of comprehensive analyses. To address this deficit we generated ten SAGE libraries from the developing murine pancreas spanning Theiler stages 17-26, making use of available Pdx1 enhanced green fluorescent protein (EGFP) and Neurog3 EGFP reporter strains, as well as tissue from adult islets and ducts.

    Results: We used a specificity metric to identify 2,536 tags with pancreas-enriched expression compared to 195 other mouse SAGE libraries. We subsequently grouped co-expressed transcripts with differential expression during pancreas development using K-means clustering. We validated the clusters first using quantitative real time PCR and then by analyzing the Theiler stage 22 pancreas in situ hybridization staining patterns of over 600 of the identified genes using the GenePaint database. These were then categorized into one of the five expression domains within the developing pancreas. Based on these results we identified a cascade of transcriptional regulators expressed in the endocrine pancreas lineage and, from this, we developed a predictive regulatory network describing beta-cell development.

    Conclusion: Taken together, this work provides evidence that the SAGE libraries generated here are a valuable resource for continuing to elucidate the molecular mechanisms regulating pancreas development. Furthermore, our studies provide a comprehensive analysis of pancreas development, and insights into the regulatory networks driving this process are revealed.

    Genome biology 2008;9;6;R99

  • EUCOMM--the European conditional mouse mutagenesis program.

    Friedel RH, Seisenberger C, Kaloff C and Wurst W

    GSF-National Research Center for Environment and Health, Institute of Developmental Genetics, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany.

    Functional analysis of the mammalian genome is an enormous challenge for biomedical scientists. To facilitate this endeavour, the European Conditional Mouse Mutagenesis Program (EUCOMM) aims at generating up to 12 000 mutations by gene trapping and up to 8000 mutations by gene targeting in mouse embryonic stem (ES) cells. These mutations can be rendered into conditional alleles, allowing Cre recombinase-mediated disruption of gene function in a time- and tissue-specific manner. Furthermore, the EUCOMM program will generate up to 320 mouse lines from the EUCOMM resource and up to 20 new Cre driver mouse lines. The EUCOMM resource of vectors, mutant ES cell lines and mutant mice will be openly available to the scientific community. EUCOMM will be one of the cornerstones of an international effort to create a global mouse mutant resource.

    Briefings in functional genomics & proteomics 2007;6;3;180-5

  • Mutations in FGD4 encoding the Rho GDP/GTP exchange factor FRABIN cause autosomal recessive Charcot-Marie-Tooth type 4H.

    Delague V, Jacquier A, Hamadouche T, Poitelon Y, Baudot C, Boccaccio I, Chouery E, Chaouch M, Kassouri N, Jabbour R, Grid D, Mégarbané A, Haase G and Lévy N

    INSERM U491, Génétique Médicale et Développement, Faculté de Médecine de la Timone, Marseille, France. valerie.delague@medecine.univ-mrs.fr

    Charcot-Marie-Tooth (CMT) disorders are a clinically and genetically heterogeneous group of hereditary motor and sensory neuropathies characterized by muscle weakness and wasting, foot and hand deformities, and electrophysiological changes. The CMT4H subtype is an autosomal recessive demyelinating form of CMT that was recently mapped to a 15.8-Mb region at chromosome 12p11.21-q13.11, in two consanguineous families of Mediterranean origin, by homozygosity mapping. We report here the identification of mutations in FGD4, encoding FGD4 or FRABIN (FGD1-related F-actin binding protein), in both families. FRABIN is a GDP/GTP nucleotide exchange factor (GEF), specific to Cdc42, a member of the Rho family of small guanosine triphosphate (GTP)-binding proteins (Rho GTPases). Rho GTPases play a key role in regulating signal-transduction pathways in eukaryotes. In particular, they have a pivotal role in mediating actin cytoskeleton changes during cell migration, morphogenesis, polarization, and division. Consistent with these reported functions, expression of truncated FRABIN mutants in rat primary motoneurons and rat Schwann cells induced significantly fewer microspikes than expression of wild-type FRABIN. To our knowledge, this is the first report of mutations in a Rho GEF protein being involved in CMT.

    American journal of human genetics 2007;81;1;1-16

  • Peripheral nerve demyelination caused by a mutant Rho GTPase guanine nucleotide exchange factor, frabin/FGD4.

    Stendel C, Roos A, Deconinck T, Pereira J, Castagner F, Niemann A, Kirschner J, Korinthenberg R, Ketelsen UP, Battaloglu E, Parman Y, Nicholson G, Ouvrier R, Seeger J, De Jonghe P, Weis J, Krüttgen A, Rudnik-Schöneborn S, Bergmann C, Suter U, Zerres K, Timmerman V, Relvas JB and Senderek J

    Institute of Cell Biology, ETH Zürich, Schafmattstrasse 18, CH-8093 Zürich, Switzerland. claudia.stendel@cell.biol.ethz.ch

    GTPases of the Rho subfamily are widely involved in the myelination of the vertebrate nervous system. Rho GTPase activity is temporally and spatially regulated by a set of specific guanine nucleotide exchange factors (GEFs). Here, we report that disruption of frabin/FGD4, a GEF for the Rho GTPase cell-division cycle 42 (Cdc42), causes peripheral nerve demyelination in patients with autosomal recessive Charcot-Marie-Tooth (CMT) neuropathy. These data, together with the ability of frabin to induce Cdc42-mediated cell-shape changes in transfected Schwann cells, suggest that Rho GTPase signaling is essential for proper myelination of the peripheral nervous system.

    American journal of human genetics 2007;81;1;158-64

  • Quantitative trait loci linked to thalamus and cortex gray matter volumes in BXD recombinant inbred mice.

    Dong H, Martin MV, Colvin J, Ali Z, Wang L, Lu L, Williams RW, Rosen GD, Csernansky JG and Cheverud JM

    Department of Psychiatry, Washington University School of Medicine, St Louis, MO 63110, USA. dongh@wustl.edu

    To investigate whether there are separate or shared genetic influences on the development of the thalamus and cerebral cortex, we identified quantitative trait loci (QTLs) for relevant structural volumes in BXD recombinant inbred (RI) strains of mice. In 34 BXD RI strains and two parental strains (C57BL/6J and DBA/2J), we measured the volumes of the entire thalamus and cortex gray matter using point counting and Cavalieri's rule. Heritability was calculated using analysis of variance (ANOVA), and QTL analysis was carried out using WebQTL (http://www.genenetwork.org). The heritability of thalamus volume was 36%, and three suggestive QTLs for thalamus volume were identified on chromosomes 10, 11 and 16. The heritability of cortical gray matter was 43%, and four suggestive QTLs for cortex gray matter volume were identified on chromosomes 2, 8, 16 and 19. The genetic correlation between thalamus and cortex gray matter volumes was 0.64. Also, a single QTL on chromosome 16 (D16Mit100) was identified for thalamus volume, cortex gray matter volume and Morris water maze search-time preference (r=0.71). These results suggest that there are separate and shared genetic influences on the development of the thalamus and cerebral cortex.

    Funded by: NCI NIH HHS: U01 CA105417, U01CA105417; NIAAA NIH HHS: U01 AA013499, U01 AA013513, U01 AA014425, U01AA014425, U01AA13499, U24AA13513; NIDA NIH HHS: P20 DA021131, P20-DA 21131; NIDDK NIH HHS: P30 DK056341; NIMH NIH HHS: MH071616, P50 MH071616; NINR NIH HHS: U01NR 105417

    Heredity 2007;99;1;62-9

  • Quantitative trait loci for body size components in mice.

    Kenney-Hunt JP, Vaughn TT, Pletscher LS, Peripato A, Routman E, Cothran K, Durand D, Norgard E, Perel C and Cheverud JM

    Department of Anatomy and Neurobiology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA. jpkenney@artsci.wustl.edu

    Do body size components, such as weights of internal organs and long bone lengths, with different functions and different developmental histories also have different genetic architectures and pleiotropic patterns? We examine murine quantitative trait loci (QTL) for necropsy weight, four long bone lengths, and four organ weights in the LG/J x SM/J intercross. Differences between trait categories were found in number of QTL, dominance, and pleiotropic patterns. Ninety-seven QTLs for individual traits were identified: 52 for long bone lengths, 30 for organ weights, and 15 for necropsy weight. Results for long bones are typically more highly significant than for organs. Organ weights were more frequently over- or underdominant than long bone lengths or necropsy weight. The single-trait QTLs map to 35 pleiotropic loci. Long bones are much more frequently affected in groups while organs tend to be affected singly or in pairs. Organs and long bones are found at the same locus in only 11 cases, 8 of which also include necropsy weight. Our results suggest mainly separate genetic modules for organ weights and long bone lengths, with a few loci that affect overall body size. Antagonistic pleiotropy, in which a locus has opposite effects on different characteristics, is uncommon.

    Funded by: NCRR NIH HHS: RR 15116; NHLBI NIH HHS: HL 58427; NIDDK NIH HHS: DK 52514, DK 55736, P30 DK056341, P30 DK056341-05S2, P30 DK056341-06

    Mammalian genome : official journal of the International Mammalian Genome Society 2006;17;6;526-37

  • BGEM: an in situ hybridization database of gene expression in the embryonic and adult mouse nervous system.

    Magdaleno S, Jensen P, Brumwell CL, Seal A, Lehman K, Asbury A, Cheung T, Cornelius T, Batten DM, Eden C, Norland SM, Rice DS, Dosooye N, Shakya S, Mehta P and Curran T

    Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States.

    Funded by: NINDS NIH HHS: 5R37NS036558, N01-NS-0-2331, R37 NS036558

    PLoS biology 2006;4;4;e86

  • 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

  • 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

  • Association of frabin with specific actin and membrane structures.

    Kim Y, Ikeda W, Nakanishi H, Tanaka Y, Takekuni K, Itoh S, Monden M and Takai Y

    Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine/Faculty of Medicine, Suita 565-0871, Japan.

    Background: Frabin is an actin filament (F-actin)-binding protein with GDP/GTP exchange activity specific for Cdc42 small G protein. Expression of frabin forms filopodia-like microspikes through the direct activation of Cdc42, and lamellipodia through indirect activation of Rac small G protein. Frabin consists of the F-actin-binding domain (FAB), the Dbl homology domain (DH), the first pleckstrin homology domain (PH1), the FYVE-finger domain (FYVE), the second PH domain (PH2) from the N-terminus in this order. Although DH and PH1 show exchange activity, FAB, in addition to DH and PH1, is required for the formation of microspikes, whereas FYVE and PH2, in addition to DH and PH1, are required for the formation of lamellipodia.

    Results: Various truncated mutants of frabin were co-expressed with a dominant active mutant (DA) of Cdc42, Rac1DA, or full-length frabin in L fibroblasts. FAB was recruited to the Cdc42DA-formed filopodia-like microspikes. FAB and a fragment containing DH, PH1, FYVE and PH2 were recruited to the Rac1DA-formed membrane ruffles. Furthermore, each of these fragments served as a dominant negative mutant of frabin when co-expressed with full-length frabin, and inhibited the full-length frabin-formed morphological changes.

    Conclusion: These results suggest that frabin recognizes a specific actin structure(s) through FAB and a specific membrane structure(s) through FAB and the region containing DH, PH1, FYVE and PH2. It is likely that frabin associates with the specific actin and membrane structures and activates Cdc42 and Rac in the vicinity of these structures, eventually leading to morphological changes.

    Genes to cells : devoted to molecular & cellular mechanisms 2002;7;4;413-20

  • Identification of splicing variants of Frabin with partly different functions and tissue distribution.

    Ikeda W, Nakanishi H, Takekuni K, Itoh S and Takai Y

    Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine/Faculty of Medicine, Suita, 565-0871, Japan.

    Frabin is a GDP/GTP exchange protein for Cdc42 small G protein with actin filament-binding activity. Frabin consists of the actin filament-binding domain, the Dbl homology domain, the first pleckstrin homology domain, the FYVE-finger domain, and the second pleckstrin homology domain in this order from the N-terminus. Frabin forms filopodia through direct activation of Cdc42 and lamellipodia through indirect activation of Rac small G protein. We isolated here two smaller splicing variants of frabin and named the original one, middle-size one, and smallest one frabin-alpha, -beta, and -gamma, respectively. Frabin-beta lacked the second pleckstrin homology domain and frabin-gamma lacked the FYVE-finger domain and the second pleckstrin homology domain. These three variants were expressed in all of the tissues examined but their expression levels are different depending on tissues. In L fibroblasts, all the three variants formed filopodia. As to lamellipodia, frabin-alpha formed them; frabin-beta formed them to a small extent; and frabin-gamma did not. In MDCK epithelial cells, frabin-alpha formed microspikes but frabin-beta or -gamma did not.

    Biochemical and biophysical research communications 2001;286;5;1066-72

  • Two actions of frabin: direct activation of Cdc42 and indirect activation of Rac.

    Ono Y, Nakanishi H, Nishimura M, Kakizaki M, Takahashi K, Miyahara M, Satoh-Horikawa K, Mandai K and Takai Y

    Takai Biotimer Project, ERATO, Japan Science and Technology Corporation, c/o JCR Pharmaceuticals Co. Ltd., 2-2-10 Murotani, Nishi-ku, Kobe 651-2241, Japan.

    Frabin is an actin filament-binding protein which shows GDP/GTP exchange activity specific for Cdc42 small G protein and induces filopodium-like microspike formation and c-Jun N-terminal kinase (JNK) activation presumably through the activation of Cdc42. Frabin has one actin filament-binding (FAB) domain, one Dbl homology (DH) domain, first pleckstrin homology (PH) domain adjacent to the DH domain, one cysteine-rich FYVE domain, and second PH domain from the N-terminus to the C-terminus in this order. Different domains of frabin are involved in the microspike formation and the JNK activation, and the association of frabin with the actin cytoskeleton through the FAB domain is necessary for the microspike formation, but not for the JNK activation. We have found here that frabin induces the formation of not only filopodium-like microspikes but also lamellipodium-like structures in NIH3T3 and L fibroblasts. We have analysed the mechanism of frabin in these two actions and found that frabin induces filopodium-like microspike formation through the direct activation of Cdc42 and lamellipodium-like structure formation through the Cdc42-independent indirect activation of Rac small G protein. The FAB domain of frabin in addition to the DH domain and the first PH domain is necessary for the filopodium-like microspike formation, but not for the lamellipodium-like structure formation. The FYVE domain and the second PH domain in addition to the DH domain and the first PH domain are necessary for the lamellipodium-like structure formation. We show here these two actions of frabin in the regulation of cell morphology.

    Oncogene 2000;19;27;3050-8

  • Frabin, a novel FGD1-related actin filament-binding protein capable of changing cell shape and activating c-Jun N-terminal kinase.

    Obaishi H, Nakanishi H, Mandai K, Satoh K, Satoh A, Takahashi K, Miyahara M, Nishioka H, Takaishi K and Takai Y

    Takai Biotimer Project, ERATO, Japan Science and Technology Corporation, c/o JCR Pharmaceuticals Co., Ltd., 2-2-10 Murotani, Nishi-ku, Kobe 651-2241, Japan.

    We purified from rat brain a novel F-actin-binding protein with a Mr of about 105,000 (p105), which was estimated by SDS-polyacrylamide gel electrophoresis. We cloned its cDNA from a rat brain cDNA library and characterized it. p105 was a protein of 766 amino acids and showed a calculated Mr of 86,449. p105 consisted of one F-actin-binding domain at the N-terminal region, one Dbl homology domain and one pleckstrin homology domain at the middle region, and one cysteine-rich domain at the C-terminal region. This domain organization of p105 was similar to that of FGD1, which has been determined to be the genetic locus responsible for faciogenital dysplasia or Aarskog-Scott syndrome. We therefore named p105 frabin (FGD1-related F-actin-binding protein). Frabin bound along the sides of F-actin and showed F-actin-cross-linking activity. Overexpression of frabin in Swiss 3T3 cells and COS7 cells induced cell shape change and c-Jun N-terminal kinase activation, respectively, as described for FGD1. Because FGD1 has been shown to serve as a GDP/GTP exchange protein for Cdc42 small G protein, it is likely that frabin is a direct linker between Cdc42 and the actin cytoskeleton.

    The Journal of biological chemistry 1998;273;30;18697-700

Gene lists (3)

Gene List Source Species Name Description Gene count
L00000007 G2C Mus musculus Mouse NRC Mouse NRC adapted from Collins et al (2006) 186
L00000008 G2C Mus musculus Mouse PSP Mouse PSP adapted from Collins et al (2006) 1121
L00000021 G2C Mus musculus Pocklington M3 Cluster 3 (mouse) from Pocklington et al (2006) 30
© 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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