Figure 1. BMP2 and -4 promote enteric neuronal differentiation in early fetal development and glia at later stages and then dependence on other factors for their survival.
When ENCDC (in gray) are immunoselected at early fetal stages (E12, left) and grown for several days in vitro (DIV), BMP signaling promotes cell cycle exit and rapid neuronal differentiation, neuritic extension and clustering via PSA-NCAM of Ret and pgp9.5-expressing neurons (in green). In a subset of neurons (in red), BMP 2 or -4 promote precocious expression of TrkC, the specific transducing receptor for NT-3 (bottom left). However prolonged treatment with high BMP (20-100 ng/ml) does not sustain neuronal survival, and by E14 differentiated neurons become dependent on other neurotrophic factors (i.e. NT-3) for survival and undergo apoptosis in the absence of those factors (bottom center). High BMP concentrations interfere with the proliferative effects (green circular arrows) of GDNF. However with lower concentrations (0.1-1 ng/ml) and prolonged treatment, BMP2 or -4 increase neuronal differentiation, and this effect is enhanced by GDNF (center left). When ENCDC are immunoselected at later stages (E14 and thereafter) BMP 2 or -4 up-regulate expression of ErbB3, the specific binding receptor for GGF-2 in glial precursors that express BMP receptors, p75 NTR and Sox10 (gray cells, bottom right). As GGF-2 expression becomes maximal (by E15), ErbB3-expressing glial precursors proliferate with GGF-2 (brown circular arrows) and differentiate into mature glia (BFABP-S100β-GFAP-expressing) (right). The differentiated ErbB3-expressing glial cells (in brown) become dependent upon GGF-2 for their survival and undergo apoptosis in the absence of GGF-2 (bottom far right). High concentrations of BMP2 or -4 dampen the proliferative effects of GGF-2.