Figure 6.

Differentiation of neural crest cell-derived neuronal precursors is induced by intrinsic and extrinsic factors. (A) Bone morphogenetic proteins (BMPs) secreted by epicardial cells and vascular cells induce differentiation of NCCs to sympathetic neurons by initiating the expression of paired-like homeobox (PHOX)-2B and mammalian achaete-scute homolog (MASH)-1 in the NCCs. PHOX2B induces the expression of tyrosine hydroxylase (TH) via GATA3, and has a positive effect on MASH1 expression. MASH1 and PHOX2B both induce the expression of dopamine-β-hydroxylase (DBH) through PHOX2A and heart and neural crest derivatives expressed 2 (HAND2), the latter being essential for sympathetic differentiation; (B) The expression of Gata3 and HAND2 is lost in parasympathetic precursors, as is the downstream expression of TH and DBH. The expression of parasympathetic markers ChAT and VAChT is probably regulated via glial cell line-derived neurotrophic factor (GDNF)/Ret. OFT = outflow tract, SMC = smooth muscle cell.