NSCL-1 and -2 control the formation of precerebellar nuclei by orchestrating the migration of neuronal precursor cells

During embryonic development post-mitotic neurons of the precerebellar neuroepithelium, migrate from the rhombic lip to the ventral part of the neural tube to form the precerebellar nuclei of the pons and medulla oblongata. In this study, we show that neural basic helix-loop-helix transcription factors NSCL-1 and -2 are expressed in all cells of the anterior extramural migration stream (aes), which forms the precerebellar nuclei. The combined inactivation of NSCL-1 and -2 led to a complete absence of the pontine nuclei and a strong reduction in the reticulotegmental nuclei. We demonstrate that NSCL-1/2 were required for a sustained expression of the netrin receptor and cell guidance molecule Dcc in the aes. Unc5H3, a second netrin receptor, which serves as a stop signal for migratory cells was up-regulated in NSCL-1/2 deficient cells, which ceased migration and accumulated ectopically. Furthermore, we observed a massive increase of apoptosis in cells of the aes in the absence of NSCL-1/2, which together with the arrest of migration might explain the virtually complete loss of aes-derived structures in NSCL-1/2 mutant mice. We conclude that NSCL-1/2 maintain migration and survival of cells in the aes.