GDNF Signaling Levels Control Migration and Neuronal Differentiation of Enteric Ganglion Precursors
GDNF Signaling Levels Control Migration and Neuronal Differentiation of Enteric Ganglion Precursors
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DOI：
10.1523/jneurosci.2079-13.2013
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发表时间：
2013-10-09
影响因子：
5.3
通讯作者：
Enomoto, Hideki
中科院分区：
文献类型：
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作者：
Uesaka, Toshihiro;Nagashimada, Mayumi;Enomoto, Hideki
多效性生长因子在胚胎发育的连续过程中发挥着许多关键作用；然而，单一调节因子能够协调不同发育事件的机制仍不完全清楚。在肠神经系统(ENS)的发育过程中，最初形成肌间神经节(MGs)，之后未成熟的ENS前体从肌层向内迁移形成粘膜下神经节(SMGs)。在这里，我们证明了胶质细胞系衍生神经营养因子(GDNF)不仅对于MG的形成是必不可少的，而且对于SMGs的形成也是必不可少的，从而在小鼠模型中确立GDNF作为一种长期作用的神经营养因子来促进ENS的发育。GDNF促进SMG前体的径向迁移。有趣的是，肌层中的迁移前SMG前体细胞与周围神经分化细胞的区别在于它们对GDNF介导的MAPK通路的激活程度较低，这表明GDNF下游通路的低激活是维持未成熟状态所必需的。在妊娠中期缺乏GDNF信号的ENS前体细胞停止迁移，存活，并在体内长期保持未分化状态。在肠道器官培养中，重新激活这些休眠前体细胞上的GDNF信号可以恢复它们的迁移和神经元分化。这些发现表明，GDNF的多效性功能至少部分是由GDNF下游通路的细胞内激活水平控制的；高激活触发神经元分化，而低激活对维持祖细胞状态至关重要。
Pleiotropic growth factors play a number of critical roles in continuous processes of embryonic development; however, the mechanisms by which a single regulatory factor is able to orchestrate diverse developmental events remain imperfectly understood. In the development of the enteric nervous system (ENS), myenteric ganglia (MGs) form initially, after which the submucosal ganglia (SMGs) develop by radial inward migration of immature ENS precursors from the myenteric layer. Here, we demonstrate that glial cell line-derived neurotrophic factor (GDNF) is essential for the formation not only of the MGs, but the SMGs as well, establishing GDNF as a long-term acting neurotrophic factor for ENS development in a mouse model. GDNF promotes radial migration of SMG precursors. Interestingly, premigratory SMG precursors in the myenteric layer were distinguished from the surrounding neuronally differentiating cells by their lower activation of the GDNF-mediated MAPK pathway, suggesting that low activation of GDNF downstream pathways is required for the maintenance of the immature state. ENS precursors devoid of GDNF signaling during midgestation halt their migration, survive, and remain in an undifferentiated state over the long-term in vivo. Reactivation of GDNF signaling in these dormant precursors restores their migration and neuronal differentiation in gut organ culture. These findings suggest that pleiotropic function of GDNF is at least in part governed by modulating levels of intracellular activation of GDNF downstream pathways; high activation triggers neuronal differentiation, whereas low activation is crucial for the maintenance of progenitor state.