Isolation, characterization, and mapping of the mouse Fgd3 gene, a new Faciogenital Dysplasia (FGD1; Aarskog Syndrome) gene homologue.
FGD1 gene mutations result in faciogenital dysplasia (FGDY, Aarskog syndrome), an X-linked developmental disorder that adversely affects the formation of multiple skeletal structures. FGD1 encodes a guanine nucleotide exchange factor (GEF) that specifically activates the Rho GTPase Cdc42. By way of Cdc42, FGD1 regulates the actin cytoskeleton and activates the c-Jun N-terminal kinase signaling cascade to regulate cell growth and differentiation. Previous work shows that FGD1 is the founding member of a family of related genes including the mouse Fgd2 gene and the rat Frabin gene. Here, we report on the isolation, characterization, and mapping of the mouse Fgd3 gene, a new and novel member of the FGD1 gene family. Fgd3 cDNA encodes a 733-amino-acid protein with a predicted mass of 81 kDa. Fgd3 and FGD1 share a high degree of sequence identity that spans >560 contiguous amino acid residues. Like FGD1, Fgd3 contains adjacent RhoGEF and pleckstrin homology (PH) domains, a second carboxy-terminal PH domain, and a distinctive FYVE domain. Together, these domains appear to form a canonical core structure for FGD1 family members. In addition, compared to other FGD1 family members, Fgd3 contains different structural regions that may be involved in distinct signaling interactions. Microinjection studies show that Fgd3 stimulates fibroblasts to form filopodia, actin microspikes formed upon the stimulation of Cdc42. Fgd3 transcripts are present in several diverse tissues and during mouse embryogenesis, suggesting a developmentally regulated pattern of expression and a potential role in embryonic development. Genetic linkage and radiation hybrid mapping data show that Fgd3 and the human FGD3 ortholog map to syntenic regions of murine chromosome 13 and human chromosome 9q22, respectively. We conclude that Fgd3 is a new and novel member of the FGD1 family of RhoGEF proteins.
Pasteris
N G
NG
Department of Pediatrics, University of Michigan Medical School, Ann Arbor 48109-0688, USA.
Nagata
K
K
Hall
A
A
Gorski
J L
JL
D016475:3T3 Cells; D000015:Abnormalities, Multiple / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D002875:Chromosomes / Q000235:genetics; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D018076:DNA, Complementary / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification*; D005147:Facial Bones / Q000002:abnormalities; D018507:Gene Expression Regulation, Developmental; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009115:Muridae; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D064067:Rho Guanine Nucleotide Exchange Factors; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D014018:Tissue Distribution; D014564:Urogenital Abnormalities / Q000235:genetics; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
D018076:DNA, Complementary; C490796:FGD1 protein, human; C097489:Fgd1 protein, mouse; C405927:Fgd3 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D011506:Proteins; D012333:RNA, Messenger; D064067:Rho Guanine Nucleotide Exchange Factors; D020764:cdc42 GTP-Binding Protein