Bone morphogenetic proteins contribute to peripheral nervous system development by negatively regulating glial differentiation

During vertebrate development, numerous intrinsic and extrinsic factors give rise to the structures and cell types of the intact, functionally diverse nervous system. These include cell-to-cell interactions, cell autonomous genetic programs as well as exposure to combinations of soluble cues that a differentiating cell encounters in the extracellular milieu. One of the most fundamental challenges facing developmental biologists is identifying which soluble factors encountered by a migrating, neural crest-derived stem cell dictate the cell's fate and understanding how the timing, concentration and extent of exposure to these factors influence a cell to adopt a particular lineage.; Bone morphogenetic proteins are members of the transforming growth factor-beta (TGF-beta) superfamily that play roles in numerous developmental processes. In the nervous system, BMPs promote the differentiation of neurons from neural crest stem cells (NCSCs). Despite this well-defined role of BMPs as neurogenic factors, little is known about the role BMPs play in glial differentiation. I have investigated the role of BMPs in glial lineage commitment and maturation using a neural crest-derived cell line resembling immature glia. Compelling evidence is provided that BMPs exert an inhibitory effect on glial maturation. This regulation is mediated through both canonical and novel signal transduction pathways downstream of the BMP receptor and results in maintained expression of a subset of immature glial genes and an inhibition of the morphological changes and gene expression patterns associated with glial maturation. Evidence is also provided that a glial-specific gene, glial fibrillary acidic protein (GFAP) is regulated both in-vitro and in-vivo by BMPs and that its expression pattern parallels that of several well defined stem cell-associated genes. These findings suggest that BMPs may simultaneously promote neurogenesis while negatively regulating glial differentiation. These contrasting effects of BMPs on different neural crest lineages demonstrate one way in which neural diversity is differentially influenced by a single soluble factor during neural patterning and development.