Bone morphogenetic proteins (BMPs) have been implicated as control factors in many different developmental transitions. During nervous system development BMPs regulate neural induction, formation of the neural crest, and the development of both neurons and glia. Within individual neural lineages, BMPs control progressive developmental decisions, reflecting changes in cellular responses to BMPs over time. In the peripheral nervous system BMPs increase neuronal differentiation of neural crest cells and later promote the maturation of enteric and sympathetic neurons along lineage-specific pathways. The goal of this proposal is to determine the cellular and molecular mechanisms underlying the developmental actions of BMPs during the divergence of the enteric and sympathetic nervous systems and to investigate the basis of changing BMP responsiveness. We will determine the role of BMPs in regulating developmental transitions of multipotent precursor cells, committed neuronal progenitors, and developing glial cells. We will test the hypothesis that BMP2 promotes neuronal differentiation by maintaining a pool of uncommitted precursor cells at the expense of glial differentiation and that BMP signaling contributes to the timing of neuron and glial development in the peripheral nervous system. A role for BMPs in the divergence of the enteric and sympathetic lineages and the maturation of specific neuronal subtypes will be examined and we will test the idea that BMP signaling contributes to the acquisition of functional neuronal properties in vitro and in the animal. BMP responses depend upon the pattern of transcriptional activation set up through expression of specific transcription factors. We will use DNA microarrays to define BMP-induced changes in patterns of transcription factor gene expression at different developmental stages. The integration of cellular and transcriptional analysis of BMP function and the use of a novel inducible transgenic mouse system for the regulation of BMP signaling in vivo will result in a new understanding of the regulatory circuits that contribute to the divergence and maturation of peripheral neuron lineages.
