Perspectives on integration of cell extrinsic and cell intrinsic pathways of signaling required for differentiation of noradrenergic sympathetic ganglion neurons

This review presents an analysis of current research aimed at deciphering the interplay of cell extrinsic and intrinsic signals required for specification and differentiation of noradrenergic sympathetic ganglion neurons. The development of noradrenergic sympathetic ganglion neurons depends upon expression of a core set of DNA regulatory molecules, including the Phox2 homeodomain proteins and the basic helix–loop–helix proteins, HAND2 and MASH1 whose expression is dependent upon cell extrinsic cues. Both bone morphogenetic protein(s) and cAMP have an integral role in the specification/differentiation of noradrenergic sympathetic ganglion neurons but how signaling downstream of these molecules is integrated and identification of their particular functions is just beginning to be elucidated. Data currently available suggests a model with BMP providing both instructive and permissive cues in a pathway integrated by cAMP and MAPK by activation of both canonical and non-canonical intracellular signaling cascades.