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.Cell adhesion molecules are essential for the regulation of coordinated changes in cell shape and position that occur during morphogenesis and also for the maintenance of cell-cell interactions once development is complete. The best-studied families of cell adhesion molecules are the cadherins. These were originally identified as Ca 2ϩ -dependent cell-cell adhesion proteins characterized by five repeated cadherin-specific motifs in their extracellular domain. This domain is an approximately 110-amino-acid peptide that mediates homophilic interactions with other cadherin molecules, forming dimers which then interact with dimers on neighboring cells (41,45,46). The cytoplasmic domain of these so-called classical fiverepeat cadherins is well conserved between different members of the family, containing motifs required for interaction with catenins that can then mediate linkage to the cytoskeleton (13,17,34,42). In addition to the classical cadherins, at least five other classes of cadherins have been identified: nonclassical cadherins, in which the first extracellular repeat does not contain the HAV (histidine-alanine-valine) cell adhesion sequence present in all classical cadherins, and four additional families. Two of these, the desmosomal adhesion molecules desmocollins and desmogleins, all share the five extracellular cadherin repeat structure with the sole exception of desmocollin-1. Two other families, the flamingo cadherins and protocadherins, have variable numbers of cadherin repeats and additional motifs as well as differing cytoplasmic domain sequences (30,44).