Bone morphogenetic protein signaling mediated neuronal differentiation

The bone morphogenetic proteins (BMPs) belong to the transforming growth factor superfamily of secreted signaling molecules. BMPs signal by binding to the type I (BMPR1A, BMPR1B and ALK2) and type II (BMPR2) receptors that phosphorylate downstream molecules like the SMADs which translocate to the nucleus and regulate gene transcription. In development BMPs are involved in multiple processes including progenitor patterning, lineage commitment, exit from cell cycle, differentiation and apoptosis in different organ systems. Here we investigate the role of BMP signaling in the differentiation of neuronal subtypes in the different regions of the nervous system. First, we examine the role of BMPs in the differentiation of two distinct subtypes of cortical interneurons that are derived from the medial ganglionic eminences and can be distinguished by their expression of parvalbumin and somatostatin respectively. We find that a subpopulation of committed interneuron precursors migrate to the cortex and differentiate into parvalbumin expressing interneurons in the presence of the BMP ligand BMP4. BMP4 also inhibits the differentiation of somatostatin expressing interneurons from their precursors and these effects are mediated by type I receptors BMPR1A and BMPR1B. Next, we investigate the role of BMP signaling in the differentiation of neuronal subtypes in the hypothalamus that originate from OLIG1 expressing progenitors. We show that multiple populations of dopaminergic neurons in the hypothalamus are derived from the OLIG1 expressing progenitors and they depend on BMP signaling mediated by BMPR1A for their differentiation. Loss of the dopaminergic neuron populations in the hypothalamus causes severe preweaning anorexia in mice that is phenotypically identical to mice mutants that are unable to synthesize dopamine in their dopaminergic neurons. Finally, we examine the role of the BMP regulated transcription factor HeyL in the neuronal differentiation in the peripheral nervous system by generating mice mutant for HeyL. Our results indicate that HeyL mediates the differentiation of a subpopulation of neurons in the dorsal root ganglia that express the neurotrophin receptor TrkC by antagonizing the Hey paralog Hey1. Overall, our findings support a role for BMP signaling in the neuronal differentiation process in multiple regions of the nervous system.