Signaling networks that regulate sympathoadrenal cell development in cultured primary neural crest cells

Cells of the vertebrate neural crest (crest cells) are an invaluable model system to address cell fate specification. Crest cells are amenable to tissue culture, and they differentiate to a variety of neuronal and non-neuronal cell types. Independent studies determined that the bone morphogenetic protein (BMP) and cAMP signaling pathways stimulate development of the sympathoadrenal (SA) lineage in neural crest cultures, however, the combinatorial effect of these signaling pathways remains to be explored. Interactive mechanisms between the BMP-2 and cAMP signaling pathways were tested using cultures of primary neural crest cells derived from the trunk region of Japanese quail. These investigations demonstrated that cAMP signaling functions as a bimodal switch on SA cell development. Moderate activation of the cAMP signaling pathway promotes, in synergy with BMP-2, SA cell development and the selective expression of the SA lineage-determining gene Phox2a. By contrast, robust activation of the cAMP signaling pathway opposes, even in the presence of BMP-2, SA cell development and the expression of the SA lineage-determining ASH-1 and Phox2 genes. ^ The synergy of the combined BMP-2 and cAMP signals appears to be derived from their instructive influences at temporally distinct points in the developmental program of the SA lineage. These results agree with the general principle that neuronal diversity is generated through progressive restriction of the developmental potential of initially totipotent stem cells, via the combinatorial effects of lineage-determining transcription factors (e.g., ASH-1) and general transcription factors (e.g., CREB). The antagonism of SA cell development by the cAMP signaling pathway requires activation of the extracellular-signal regulated kinase cascade, suggesting that the dual function of the cAMP signaling pathway is related to a differential activation of signaling networks. ^