Multiple Signaling Pathways Converge to Regulate Bone-Morphogenetic-Protein-Dependent Glial Gene Expression

A fundamental problem in developmental neuroscience is understanding how extracellular cues link to complex intracellular signaling pathways to drive stage-specific developmental decisions. During the formation of the mammalian peripheral nervous system, bone morphogenetic proteins (BMPs) promote neuronal differentiation. BMPs also maintain the expression of early glial genes such as GFAP, while blocking the acquisition of a mature, myelinating Schwann cell phenotype. We investigated the BMP-activated signaling pathways that contribute to early glial gene expression to address the question of how specific signaling interactions contribute to cell fate decisions in neural crest lineages. Using a neural-crest-derived cell line that exhibits the characteristics of immature Schwann cells, we found that BMP2 promotes GFAP expression using Smad signaling as well as the phosphoinositide-3 kinase (PI3K) and mitogen-activated protein kinase1/2extracellular signal-regulated kinase- (MEK1/2/ERK) pathways. The GFAP promoter does not contain known Smad consensus sites, suggesting that Smads may act indirectly to promote GFAP expression. We provide evidence that this indirect effect may be mediated via induction of immediate early genes and the transcription factor Sp1 by demonstrating that these transcriptional regulators are induced by BMP2 and contribute to GFAP promoter activity. These findings demonstrate new roles for intracellular kinase pathways in mediating the effects of BMPs during the early stages of glial differentiation and suggest that differential contributions by signaling and transcriptional networks may contribute to the range of effects of BMPs on neuronal and glial development during the formation of the peripheral nervous system.