A cell autonomous requirement for the cell cycle regulatory RbE2F pathway in neuronal migration

Abstract

While the role of the cell cycle regulatory Rb/E2F pathway is well appreciated as a key regulator of neural precursor proliferation, here a novel role for the Rb pathway in neuronal migration is described. Using cortical slice co-culture assays a cell autonomous requirement was identified for Rb in regulating migration of ventrally derived interneurons in the developing telencephalon. Next, we sought to determine the mechanism by which Rb mediates proliferation and migration in neurogenesis. Members of the E2F transcription factor family are key Rb interacting factors, well known for mediating cell cycle regulation, whose activity is deregulated in the absence of Rb. Using mice with compound null mutations of Rb and E2F1 or E2F3, we asked to which extent either E2F interacts with Rb in neurogenesis. Here, it is reported that E2F1 and E2F3 are both functionally relevant targets in neural precursor proliferation, cell cycle exit, and laminar patterning. Neuronal migration, however, is specifically mediated through E2F3, beyond its role in cell cycle regulation. Through microarray based screening methods neogenin, a member of the neogenin-netrin pathway, was identified as a candidate E2F responsive gene, and through in vitro explant cultures a disrupted netrin mediated migration response was observed in Rb deficient interneurons. Together, these results are the first to establish a requirement for the Rb/E2F pathway beyond cell cycle regulation in nervous system development in vivo.