Wild-type and mutant forms of v-sre differentially alter neuronal migration and differentiation in vivo

The effects of three different forms of v-src on brain cell development wer e determined in vivo. Recombinant retroviral vectors encoding the marker la cZ (control) and either wild-type v-src or SH2 or SH3 domain-deleted forms of v-src (Delta SH2 or Delta SH3, respectively) were used to infect neurona l progenitor cells in the embryonic chicken midbrain (optic tectum; OT). Em bryos were injected in the OT with retroviral concentrates on embryonic day (E) 3 and sacrificed at E6, E9, and later in development. Patterns of cell proliferation, migration, and differentiation of lacZ-marked clonal cell p rogeny were then analyzed. Relative to lacZ-only controls, cell clone size at E6 was significantly increased for v-src-, unchanged for Delta SH2-, and smaller for Delta SH3-injected embryos. At E9, Delta SH2 cell clones were significantly larger than controls, suggesting increased survival from norm al programmed cell death. Radial neuronal migration was impaired for v-src and Delta SH3 clones, whereas tangential neuronal migration was enhanced al ong fiber tracts in v-src and Delta SH2 clones. Moreover, radial glial cell development and differentiation was hindered in v-src and Delta SH3 clones . These experiments demonstrate that ectopic v-src signaling alters prolife ration, migration, survival, and differentiation of developing brain cells and suggest that src signaling pathways are involved in these developmental processes. Furthermore, certain effects of v-src on brain cells require sp ecific src homology domains. (C) 2000 Wiley-Liss, Inc.