Geminin prevents DNA damage in vagal neural crest cells to ensure normal enteric neurogenesis.
Geminin prevents DNA damage in vagal neural crest cells to ensure normal enteric neurogenesis.
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DOI：
10.1186/s12915-016-0314-x
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发表时间：
2016-10-24
期刊：
影响因子：
5.4
通讯作者：
Pachnis V
中科院分区：
文献类型：
--
作者：
Konstantinidou C;Taraviras S;Pachnis V
在脊椎动物中，神经嵴（NC）产生多能和高度迁移的祖细胞，这些祖细胞分布在整个胚胎中并产生周围神经系统等结构，包括肠道的内在神经胶质网络，即肠神经系统（ENS）。大多数肠神经元和神经胶质细胞起源于迷走神经NC衍生的祖细胞，它们侵入前肠间充质并沿头尾部迁移以定殖整个肠道。尽管 NC 细胞的迁移行为已被广泛研究，但仍不清楚当它们穿过复杂的细胞地形到达目标胚胎位点时，它们的特性和对微环境的反应如何变化。通过对小鼠进行条件性基因失活，我们证明细胞周期依赖性蛋白 Geminin (Gem) 以阶段依赖性方式对于 ENS 祖细胞的生存至关重要。早期 ENS 祖细胞（前肠入侵之前）的 Gem 缺失导致细胞自主激活 DNA 损伤反应和 p53 依赖性细胞凋亡，导致严重的肠无神经节细胞症。相比之下，在 ENS 祖细胞侵入胚胎肠道后不久去除 Gem 并没有导致明显的存活或迁移缺陷。与其他发育系统相比，我们没有获得任何证据表明 Gem 在 ENS 谱系的定型或分化中发挥作用。相对于其前辈，肠道入侵后ENS谱系对γ辐射的存活率提高，进一步支持了ENS祖细胞对突变诱导的基因毒性应激的阶段依赖性抵抗力。我们的实验表明，在哺乳动物中，NC 衍生的 ENS 谱系以特定阶段的方式对基因毒性应激敏感。肠道入侵后，ENS 祖细胞与肠道前的对应物相比，对 Gem 消融和辐射具有明显的抵抗力。这些研究表明，胚胎肠道的微环境可以保护 ENS 祖细胞及其后代免受基因毒性应激。本文的在线版本 (doi:10.1186/s12915-016-0314-x) 包含补充材料，可供授权用户使用。
In vertebrate organisms, the neural crest (NC) gives rise to multipotential and highly migratory progenitors which are distributed throughout the embryo and generate, among other structures, the peripheral nervous system, including the intrinsic neuroglial networks of the gut, i.e. the enteric nervous system (ENS). The majority of enteric neurons and glia originate from vagal NC-derived progenitors which invade the foregut mesenchyme and migrate rostro-caudally to colonise the entire length of the gut. Although the migratory behaviour of NC cells has been studied extensively, it remains unclear how their properties and response to microenvironment change as they navigate through complex cellular terrains to reach their target embryonic sites. Using conditional gene inactivation in mice we demonstrate here that the cell cycle-dependent protein Geminin (Gem) is critical for the survival of ENS progenitors in a stage-dependent manner. Gem deletion in early ENS progenitors (prior to foregut invasion) resulted in cell-autonomous activation of DNA damage response and p53-dependent apoptosis, leading to severe intestinal aganglionosis. In contrast, ablation of Gem shortly after ENS progenitors had invaded the embryonic gut did not result in discernible survival or migratory deficits. In contrast to other developmental systems, we obtained no evidence for a role of Gem in commitment or differentiation of ENS lineages. The stage-dependent resistance of ENS progenitors to mutation-induced genotoxic stress was further supported by the enhanced survival of post gut invasion ENS lineages to γ-irradiation relative to their predecessors. Our experiments demonstrate that, in mammals, NC-derived ENS lineages are sensitive to genotoxic stress in a stage-specific manner. Following gut invasion, ENS progenitors are distinctly resistant to Gem ablation and irradiation in comparison to their pre-enteric counterparts. These studies suggest that the microenvironment of the embryonic gut protects ENS progenitors and their progeny from genotoxic stress. The online version of this article (doi:10.1186/s12915-016-0314-x) contains supplementary material, which is available to authorized users.
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