FRAZZLED ENCODES A DROSOPHILA MEMBER OF THE DCC IMMUNOGLOBULIN SUBFAMILY AND IS REQUIRED FOR CNS AND MOTOR AXON GUIDANCE

We have identified a Drosophila member of the deleted in colorectal ca ncer (DCC) gene family. The frazzled gene encodes transmembrane protei ns that contain four immunoglobulin C2 type domains, six fibronectin t ype III repeats, and a cytoplasmic domain of 278 amino acids. Like ver tebrate members of the DCC family, Frazzled is expressed on axons in t he embryonic central nervous system and on motor axons in the peripher y. Frazzled is also expressed on epidermis and gut epithelium. Null mu tants in frazzled are defective in axon guidance in the central nervou s system and in motor axon guidance and targeting in the periphery. Th e phenotypes strongly resemble those of a deletion of the two Drosophi la Netrin genes. We have rescued the frazzled CNS and motor axon defec ts by expressing Frazzled specifically in neurons; expression in targe t tissues does not rescue the phenotype. These data, together with ver tebrate studies showing binding of DCC to netrin, suggest that Frazzle d may function in vivo as a receptor or component of a receptor mediat ing Netrin-dependent axon guidance.