Spatiotemporal Decline of BMP Signaling Activity in Neural Progenitors Mediates Fate Transition and Safeguards Neurogenesis

Abstract

Summary: Neural progenitors undergo temporal fate transition to generate diversified neurons in stereotyped sequence during development. However, the molecular machineries driving progenitor fate change remain unclear. Here, using the cerebellum as a platform, we demonstrate that the temporal dynamics of a dorsoventral bone morphogenetic protein (BMP)/SMAD signaling gradient orchestrates the transition from early to late phase of neurogenesis. Initially, high BMP/SMAD activity in cerebellum neural progenitors transcriptionally represses the late-born interneuron fate determinant Gsx1. As development proceeds, gradual decline in SMAD activities from ventral to dorsal progenitors progressively alleviates suppression on Gsx1 and allows transition of progenitor fate. Manipulating the BMP signaling dynamics can either lead to an immediate halt or rapid acceleration of the temporal fate switch, thus unbalancing the generation of distinct neuronal populations. Our study thus demonstrates that neural progenitors possess inherent competence to produce late-born neurons, yet identity transition is mechanistically executed by precisely timed and positioned reduction of repressors for late-fate determinants. : Ma et al. demonstrate that the switch of neural progenitor identity is directed by the spatiotemporal decline of BMP/SMAD activity. Manipulation of SMAD activity, which represses the late-born neuron fate determinant, can either halt or accelerate the temporal fate switch and thus unbalances the generation of different neuronal populations. Keywords: BMP/SMAD signaling, neural progenitors, temporal fate transition, progenitor competence, Gsx1