Department of Pathology & Cell Biology, Columbia University, New York, NY 10032, USA.
Dev Biol. 2011 Feb 1;350(1):64-79. doi: 10.1016/j.ydbio.2010.11.017. Epub 2010 Nov 19.
The neural crest-derived cell population that colonizes the bowel (ENCDC) contains proliferating neural/glial progenitors. We tested the hypothesis that bone morphogenetic proteins (BMPs 2 and 4), which are known to promote enteric neuronal differentiation at the expense of proliferation, function similarly in gliogenesis. Enteric gliogenesis was analyzed in mice that overexpress the BMP antagonist, noggin, or BMP4 in the primordial ENS. Noggin-induced loss-of-function decreased, while BMP4-induced gain-of-function increased the glial density and glia/neuron ratio. When added to immunoisolated ENCDC, BMPs provoked nuclear translocation of phosphorylated SMAD proteins and enhanced both glial differentiation and expression of the neuregulin receptor ErbB3. ErbB3 transcripts were detected in E12 rat gut, before glial markers are expressed; moreover, expression of the ErbB3 ligand, glial growth factor 2 (GGF2) escalated rapidly after its first detection at E14. ErbB3-immunoreactive cells were located in the ENS of fetal and adult mice. GGF2 stimulated gliogenesis and proliferation and inhibited glial cell derived neurotrophic factor (GDNF)-promoted neurogenesis. Enhanced glial apoptosis occurred following GGF2 withdrawal; BMPs intensified this GGF2-dependence and reduced GGF2-stimulated proliferation. These observations support the hypotheses that BMPs are required for enteric gliogenesis and act by promoting responsiveness of ENCDC to ErbB3 ligands such as GGF2.
定位于肠道的神经嵴衍生细胞群体（ENCDC）包含增殖性神经/神经胶质前体细胞。我们检验了以下假说：已知骨形态发生蛋白（BMPs2 和 4）可促进肠神经元分化而抑制增殖，其在神经胶质发生中也具有相似的功能。通过在原始 ENS 中过表达 BMP 拮抗剂 noggin 或 BMP4 的小鼠来分析肠神经胶质发生。Noggin 诱导的功能丧失减少，而 BMP4 诱导的功能获得增加了神经胶质密度和神经胶质/神经元的比值。当添加到免疫分离的 ENCDC 中时，BMPs 引起磷酸化 SMAD 蛋白的核易位，并增强了神经胶质分化和神经调节蛋白受体 ErbB3 的表达。在 E12 大鼠肠道中检测到 ErbB3 转录本，在表达神经胶质标记物之前；此外，ErbB3 配体胶质细胞生长因子 2（GGF2）的表达在 E14 首次检测到后迅速增加。ErbB3 免疫反应性细胞位于胎儿和成年小鼠的 ENS 中。GGF2 刺激神经胶质发生和增殖，并抑制胶质细胞衍生神经营养因子（GDNF）促进的神经发生。GGF2 撤回后发生增强的神经胶质细胞凋亡；BMPs 加剧了这种对 GGF2 的依赖性，并减少了 GGF2 刺激的增殖。这些观察结果支持了以下假说：BMPs 是肠神经胶质发生所必需的，并且通过促进 ENCDC 对 ErbB3 配体（如 GGF2）的反应性来发挥作用。
