Memic Fatima, Knoflach Viktoria, Sadler Rebecca, Tegerstedt Gunilla, Sundström Erik, Guillemot Francois, Pachnis Vassilis, Marklund Ulrika
Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177 Stockholm, Sweden.
Department of Clinical Science, Intervention and Technology, Karolinska University Hospital, Huddinge, Karolinska Institutet, S-17177 Stockholm, Sweden.
J Neurosci. 2016 Apr 13;36(15):4339-50. doi: 10.1523/JNEUROSCI.0202-16.2016.
The enteric nervous system (ENS) is organized into neural circuits within the gastrointestinal wall where it controls the peristaltic movements, secretion, and blood flow. Although proper gut function relies on the complex neuronal composition of the ENS, little is known about the transcriptional networks that regulate the diversification into different classes of enteric neurons and glia during development. Here we redefine the role of Ascl1 (Mash1), one of the few regulatory transcription factors described during ENS development. We show that enteric glia and all enteric neuronal subtypes appear to be derived from Ascl1-expressing progenitor cells. In the gut of Ascl1(-/-) mutant mice, neurogenesis is delayed and reduced, and posterior gliogenesis impaired. The ratio of neurons expressing Calbindin, TH, and VIP is selectively decreased while, for instance, 5-HT(+) neurons, which previously were believed to be Ascl1-dependent, are formed in normal numbers. Essentially the same differentiation defects are observed in Ascl1(KINgn2) transgenic mutants, where the proneural activity of Ngn2 replaces Ascl1, demonstrating that Ascl1 is required for the acquisition of specific enteric neuronal subtype features independent of its role in neurogenesis. In this study, we provide novel insights into the expression and function of Ascl1 in the differentiation process of specific neuronal subtypes during ENS development.
The molecular mechanisms underlying the generation of different neuronal subtypes during development of the enteric nervous system are poorly understood despite its pivotal function in gut motility and involvement in gastrointestinal pathology. This report identifies novel roles for the transcription factor Ascl1 in enteric gliogenesis and neurogenesis. Moreover, independent of its proneurogenic activity, Ascl1 is required for the normal expression of specific enteric neuronal subtype characteristics. Distinct enteric neuronal subtypes are formed in a temporally defined order, and we observe that the early-born 5-HT(+) neurons are generated in Ascl1(-/-) mutants, despite the delayed neurogenesis. Enteric nervous system progenitor cells may therefore possess strong intrinsic control over their specification at the initial waves of neurogenesis.
肠神经系统（ENS）在胃肠道壁内组织成神经回路，在其中控制蠕动运动、分泌和血流。尽管肠道的正常功能依赖于ENS复杂的神经元组成，但对于在发育过程中调节分化为不同类型肠神经元和神经胶质细胞的转录网络却知之甚少。在此，我们重新定义了Ascl1（Mash1）的作用，它是在ENS发育过程中描述的少数调节转录因子之一。我们表明，肠神经胶质细胞和所有肠神经元亚型似乎都源自表达Ascl1的祖细胞。在Ascl1（-/-）突变小鼠的肠道中，神经发生延迟且减少，后部神经胶质生成受损。表达钙结合蛋白、酪氨酸羟化酶和血管活性肠肽的神经元比例选择性降低，而例如先前被认为依赖Ascl1的5-羟色胺（5-HT）能神经元数量正常形成。在Ascl1（KINgn2）转基因突变体中观察到基本相同的分化缺陷，其中神经生成蛋白2（Ngn2）的神经原活性取代了Ascl1，这表明Ascl1对于获得特定肠神经元亚型特征是必需的，与其在神经发生中的作用无关。在本研究中，我们对Ascl1在ENS发育过程中特定神经元亚型分化过程中的表达和功能提供了新的见解。
尽管肠神经系统在肠道运动中起关键作用并参与胃肠道病理过程，但其发育过程中不同神经元亚型产生的分子机制仍知之甚少。本报告确定了转录因子Ascl1在肠神经胶质生成和神经发生中的新作用。此外，独立于其神经原活性，Ascl1对于特定肠神经元亚型特征的正常表达是必需的。不同的肠神经元亚型按时间定义的顺序形成，并且我们观察到，尽管神经发生延迟，但在Ascl1（-/-）突变体中仍能产生早期生成的5-HT能神经元。因此，肠神经系统祖细胞在神经发生的初始阶段可能对其特化具有强大的内在控制。
