INTRODUCTION The migrations of neurons and their growth cones shape the structure and connectivity of developing nervous systems. Notable examples include the migrations of neural crest cells to generate the peripheral nervous system of vertebrates (Le Douarin, 1980) and the radial migrations of neurons that form the layers of the mammalian cortex (O’Rourke et al., 1992; Walsh and Cepko, 1993). In addition, extensive migrations of growth cones generate the axonal patterns of connectivity required for nervous system function (Goodman and Shatz, 1993). Growth cones and migrating cells navigate through complex environments to reach their destinations by respond- ing to guidance cues provided by other cells and the extra- cellular matrix. These cues include cell-associated molecules, immobilized matrix components and diffusible molecules. In vivo and in vitro studies have defined activities that stimulate or inhibit axon outgrowth nondirectionally, and directional activities that attract or repel migrating cells and growth cones (Reichardt and Tomaselli, 1991; Keynes and Cook, 1995). A major goal of developmental neurobiology is to understand how these cues are provided and interpreted as well as how individual cells integrate information from multiple cues. Genetic analysis of the nematode Caenorhabditis elegans has identified a guidance mechanism that provides directional information along the dorsoventral axis to migrating cells and growth cones. The product of the C. elegans gene unc-6 acts as a directional cue for both dorsally and ventrally directed migrations (Hedgecock et al., 1990; McIntire, et al., 1992). unc-6 encodes a secreted, laminin-related protein that has been proposed to be distributed in a gradient along the dorsoventral axis (Hedgecock et al., 1990; Ishii et al., 1992). The unc-5 gene is specifically required for dorsally directed migrations and appears to encode an UNC-6 receptor (Leung-Hagesteijn et al., 1992; Hamelin et al., 1993). UNC-6 is closely related to the netrins, vertebrate proteins that act in vitro as chemotropic molecules for commissural growth cones in the developing spinal cord (Tessier-Lavigne et al., 1988; Kennedy et al., 1994; Serafini et al., 1994). netrin- 1 is secreted by the ventral floor plate cells, suggesting that a gradient of netrin activity might direct commissural growth cones ventrally to the floor plate. Therefore, one cue that functions in guiding circumferential migrations appears to be functionally conserved between species (Goodman, 1994). Although components involved in directing circumferential (dorsoventral) migrations have been identified, relatively little is known about the molecules involved in directing longitudi- nal (anteroposterior) migrations. Longitudinal axon outgrowth and cell migration is a prominent feature of the development of the C. elegans nervous system. Most neuronal cell bodies in C. elegans are located in ganglia of the head and tail or ventrally along the length of the animal (Fig. 1; Albertson and Thomson, 1976; White et al., 1976, 1986). Many of these neurons extend axons along the main longitudinal nerve bundles, the ventral and dorsal nerve cords, while others extend longitudinal axons along several smaller lateral nerve bundles. 671 Development 122, 671-682 (1996) Printed in Great Britain © The Company of Biologists Limited 1996 DEV9455 The assembly of the nervous system in the nematode C. elegans requires the directed migrations of cells and growth cones along the anteroposterior and dorsoventral body axis. We show here that the gene vab-8 is essential for most posteriorly directed migrations of cells and growth cones. Mutations in vab-8 disrupt fourteen of seventeen posteri- orly directed migrations, but only two of seventeen anteri- orly directed and dorsoventral migrations. For two types of neurons that extend axons both anteriorly and posteri- orly, vab-8 mutations disrupt only the growth of the poste- riorly directed axon. vab-8 encodes two genetic activities that function in the guidance of different migrations. Our results suggest that most posteriorly directed cell and growth cone migrations are guided by a common mechanism involving the vab-8 gene. Key words: anterior-posterior axis, axon guidance, cell migration, pathfinding, C. elegans, vab-8 gene SUMMARY The C. elegans gene vab-8 guides posteriorly directed axon outgrowth and cell migration Bruce Wightman 1, *, Scott G. Clark 3 , Anna M. Taskar 1 , Wayne C. Forrester 1 , Andres V. Maricq 3 , Cornelia I. Bargmann 2,3 and Gian Garriga 1 1 Department of Molecular and Cell Biology, University of California, Berkeley, CA, 94720-3204, USA 2 Howard Hughes Medical Institute and 3 Programs in Developmental Biology, Neuroscience, and Genetics, Department of Anatomy, University of California, San Francisco, CA 94143-0452, USA *Author for correspondence (e-mail: wightman@mendel.berkeley.edu)