Rb/E2F Regulates Expression of Neogenin during Neuronal Migration

The Rb/E2F pathway has long been appreciated for its role in regulating cell cycle progression. Emerging evidence indicates that it also influences physiological events beyond regulation of the cell cycle. We have previously described a requirement for Rb/E2F mediating neuronal migration; however, the molecular mechanisms remain unknown, making this an ideal system to identify Rb/E2F-mediated atypical gene regulationin vivo . Here, we report that Rb regulates the expression ofneogenin , a gene encoding a receptor involved in cell migration and axon guidance. Rb is capable of repressing E2F-mediatedneogenin expression while E2F3 occupies a region containing E2F consensus sites on theneogenin promoter in native chromatin. Absence of Rb results in aberrant neuronal migration and adhesion in response to netrin-1, a known ligand for neogenin. Increased expression of neogenin throughex vivo electroporation results in impaired neuronal migration similar to that detected in forebrain-specific Rb deficiency. These findings show direct regulation ofneogenin by the Rb/E2F pathway and demonstrate that regulation ofneogenin expression is required for neural precursor migration. These studies identify a novel mechanism through which Rb regulates transcription of a gene beyond the classical E2F targets to regulate events distinct from cell cycle progression.