Mice lacking the giant protocadherin mFAT1 exhibit renal slit junction abnormalities and a partially penetrant cyclopia and anophthalmia phenotype.
While roles in adhesion and morphogenesis have been documented for classical cadherins, the nonclassical cadherins are much less well understood. Here we have examined the functions of the giant protocadherin FAT by generating a transgenic mouse lacking mFAT1. These mice exhibit perinatal lethality, most probably caused by loss of the renal glomerular slit junctions and fusion of glomerular epithelial cell processes (podocytes). In addition, some mFAT1(-/-) mice show defects in forebrain development (holoprosencephaly) and failure of eye development (anophthalmia). In contrast to Drosophila, where FAT acts as a tumor suppressor gene, we found no evidence for abnormalities of proliferation in two tissues (skin and central nervous system [CNS]) containing stem and precursor cell populations and in which FAT is expressed strongly. Our results confirm a necessary role for FAT1 in the modified adhesion junctions of the renal glomerular epithelial cell and reveal hitherto unsuspected roles for FAT1 in CNS development.
Departments of Medical Genetics and Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK.
Lorenza
L
Ciani
Anjla
A
Patel
Nicholas D
ND
Allen
Charles
C
ffrench-Constant
D000483:Alleles; D000818:Animals; D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000494:pharmacology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion; D002455:Cell Division; D002490:Central Nervous System / Q000196:embryology / Q000378:metabolism; D003433:Crosses, Genetic; D004330:Drosophila; D004847:Epithelial Cells / Q000166:cytology; D017930:Genes, Reporter; D005838:Genotype; D006579:Heterozygote; D020287:In Situ Nick-End Labeling; D007668:Kidney / Q000002:abnormalities* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D010641:Phenotype; D015398:Signal Transduction; D013997:Time Factors; D014018:Tissue Distribution
D015820:Cadherins; C502406:fat1 protein, mouse; D001973:Bromodeoxyuridine