The guidance of developing axons in the nervous system is mediated partly by diffusible chemoattractants secreted by axonal target cells. Netrins are chemoattractants for commissural axons in the vertebrate spinal cord, but the mechanisms through which they produce their effects are unknown. We show that Deleted in Colorectal Cancer (DCC), a transmembrane protein of the immunoglobulin superfamily, is expressed on spinal commissural axons and possesses netrin-1-binding activity. Moreover, an antibody to DCC selectively blocks the netrin-1-dependent outgrowth of commissural axons in vitro. These results indicate that DCC is a receptor or a component of a receptor that mediates the effects of netrin-1 on commissural axons, and they complement genetic evidence for interactions between DCC and netrin homologs in C. elegans and Drosophila.

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Abstract. Time-lapse photomicroscopy has been utilized to detect temperature-sensitive yeast mutants that are defective in gene functions needed at specific stages of the cell-division cycle. This technique provides two types of information about a mutant: the time at which the defective gene function is normally performed, defined as the execution point, and the stage at which cells collect when the function is not performed, defined as the termination point.Mutants carrying lesions in three genes that control the cell-division cycle are described. All three genes, cdc-1, cdc-2, and cdc-3, execute early in the cell cycle at about the time of bud initiation, but differ in their termination points. Cells carrying the cdc-1 mutation terminate at the execution point, most cells ending up with a tiny bud that does not develop further. Cells carrying the cdc-2 mutation terminate at mitosis. Cells carrying the cdc-3 mutation are defective in cell separation but show no definite termination point since other processes of the cell cycle, such as bud initiation and nuclear division, continue despite the block in cell separation.

unc-73 is required for cell migrations and axon guidance in C. elegans and encodes overlapping isoforms of 283 and 189 kDa that are closely related to the vertebrate Trio and Kalirin proteins, respectively. UNC-73A contains, in order, eight spectrin-like repeats, a Dbl/Pleckstrin homology (DH/PH) element, an SH3-like domain, a second DH/PH element, an immunoglobulin domain, and a fibronectin type III domain. UNC-73B terminates just downstream of the SH3-like domain. The first DH/PH element specifically activates the Rac GTPase in vitro and stimulates actin polymerization when expressed in Rat2 cells. Both functions are eliminated by introducing the S1216F mutation of unc-73(rh40) into this DH domain. Our results suggest that UNC-73 acts cell autonomously in a protein complex to regulate actin dynamics during cell and growth cone migrations.

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UNC-6 netrin, a laminin-related protein secreted from neuroglia and neurons along the ventral midline, orients migrating cells and pioneering growth cones on the nematode epidermis. UNC-5, a cell surface protein expressed on motile cells and pioneer axons, orients movements away from UNC-6 sources. UNC-40, a homolog of the cell surface proteins DCC (Deleted in Colorectal Cancer) and neogenin, is also expressed on motile cells and pioneer neurons. UNC-40 acts cell autonomously to orient movement toward UNC-6 sources. For cells coexpressing UNC-5, it helps orient movement away from UNC-6 sources. Finally, UNC-40 helps determine the dorsoventral position of cells undergoing purely longitudinal migrations. Together with the recent report that DCC is a netrin receptor in vertebrates, our results suggest that UNC-40 is a component of UNC-6 receptors on motile cells.

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