Institute for Advanced Biosciences, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, 38000 Grenoble, France.
Univ. Grenoble Alpes, INSERM, U1216, Grenoble Institute of Neurosciences GIN, 38000 Grenoble, France.
Sci Adv. 2019 Jul 17;5(7):eaau5106. doi: 10.1126/sciadv.aau5106. eCollection 2019 Jul.
Metabolic processes underlying the development of the neural crest, an embryonic population of multipotent migratory cells, are poorly understood. Here, we report that conditional ablation of the tumor suppressor kinase in mouse neural crest stem cells led to intestinal pseudo-obstruction and hind limb paralysis. This phenotype originated from a postnatal degeneration of the enteric nervous ganglia and from a defective differentiation of Schwann cells. Metabolomic profiling revealed that pyruvate-alanine conversion is enhanced in the absence of . Mechanistically, inhibition of alanine transaminases restored glial differentiation in an mTOR-dependent manner, while increased alanine level directly inhibited the glial commitment of neural crest cells. Treatment with the metabolic modulator AICAR suppressed mTOR signaling and prevented Schwann cell and enteric defects of mutant mice. These data uncover a link between pyruvate-alanine cycling and the specification of glial cell fate with potential implications in the understanding of the molecular pathogenesis of neural crest diseases.
神经嵴发育的代谢过程（神经嵴是一种具有多能迁移细胞的胚胎群体）知之甚少。在这里，我们报告说，条件性敲除小鼠神经嵴干细胞中的肿瘤抑制激酶会导致肠道假性肠梗阻和后肢瘫痪。这种表型源于出生后肠神经节的退化和施万细胞的分化缺陷。代谢组学分析显示，在缺乏的情况下，丙酮酸-丙氨酸转换增强。在机制上，抑制丙氨酸转氨酶以 mTOR 依赖的方式恢复神经胶质分化，而丙氨酸水平的增加直接抑制神经嵴细胞的神经胶质分化。代谢调节剂 AICAR 的治疗抑制了 mTOR 信号通路，并防止了 突变小鼠的施万细胞和肠缺陷。这些数据揭示了丙酮酸-丙氨酸循环与神经胶质细胞命运特化之间的联系，这可能对理解神经嵴疾病的分子发病机制具有重要意义。
