Human Molecular Genetics, 2001, Vol. 10, No. 26 3049-3062
© 2001 Oxford University Press
The Caenorhabditis elegans homolog of FGD1, the human Cdc42 GEF gene responsible for faciogenital dysplasia, is critical for excretory cell morphogenesis
1Department of Pediatrics and Communicable Diseases and 2Department of Human Genetics, University of Michigan School of Medicine and 3Department of Biology, College of Literature, Science and the Arts, University of Michigan, Ann Arbor, MI 48109, USA
FGD1 mutations result in faciogenital dysplasia, an X-linked human disease that affects skeletogenesis. FGD1 encodes a guanine nucleotide exchange factor (GEF) that specifically activates the Rho GTPase Cdc42. To gain insight into the function of FGD1, we have isolated and characterized fgd-1, the Caenorhabditis elegans homolog of the human FGD1 gene. Comparative sequence analyses show that fgd-1 and FGD1 share a similar structural organization and a high degree of sequence identity throughout shared signaling domains. In nematodes, interference with fgd-1 expression results in excretory cell abnormalities and cystic dilation of the excretory cell canals. Molecular lesions associated with two exc-5 alleles affect the fgd-1 gene, and fgd-1 transgenic expression rescues the Exc-5 phenotype. Together, these data confirm that the fgd-1 transcript corresponds to the exc-5 gene. Transgenic expression studies show that fgd-1 has a limited pattern of expression that is confined to the excretory cell during development, a finding that suggests that the C.elegans FGD-1 protein might function in a cell autonomous manner. Serial observations indicate that fgd-1 mutations lead to developmental excretory cell abnormalities that cause cystic dilation and interfere with canal process extension. Based on these data, we conclude that fgd-1 is the C.elegans homolog of the human FGD1 gene, a new member of the FGD1-related family of RhoGEF genes, and that fgd-1 plays a critical role in excretory cell morphogenesis and cellular organization.
+ To whom correspondence should be addressed at: Division of Pediatric Genetics, Room 3570 Medical Science Research Building II, Box 0688, University of Michigan Medical School, Ann Arbor, MI 48109-0688, USA. Tel: +1 734 647 2908; Fax: +1 734 763 9512; Email: jlgorski@med.umich.edu
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