An Isoform-Specific SnoN1-FOXO1 Repressor Complex Controls Neuronal Morphogenesis and Positioning in the Mammalian Brain

Control of neuronal positioning is fundamental to normal brain development. However, the cell-intrinsic mechanisms that govern neuronal positioning remain to be elucidated. Here, we report that the spliced protein products of the transcriptional regulator SnoN, SnoN1 and SnoN2, harbor opposing functions in the coordinate regulation of neuronal branching and positioning. Knockdown of SnoN2 stimulates axon branching in primary neurons and impairs migration of granule neurons in the rat cerebellar cortex in vivo. By contrast, SnoN1 knockdown suppresses SnoN2 knockdown-induced neuronal branching and strikingly triggers excessive migration of granule neurons in the cerebellar cortex. We also find that SnoN1 forms a complex with the transcription factor FOXO1 that represses the X-linked lissencephaly gene encoding doublecortin (DCX). Accordingly, repression of DCX mediates the ability of SnoN1 to regulate branching in primary neurons and granule neuron migration in vivo. These data define an isoform-specific SnoN1-FOXO1 transcriptional complex that orchestrates neuronal branching and positioning in the brain with important implications for the study of developmental disorders of cognition and epilepsy.