Mechanisms of neural activity during neural tube formation

项目总结 神经系统发育的第一步之一是神经板的折叠和神经板的闭合 神经管起源于大脑和脊髓。神经管形成失败导致神经管缺陷 (NTDS)，这是最常见的严重出生缺陷之一。NTDS的原因是多方面的，而且既有 已经确定了遗传和环境因素。在这些因素中，使用抗癫痫药物 在妊娠期，NTDS的发病率增加的机制不明。在成熟的神经系统中， 抗癫痫药物通过靶向不同的效应器来降低兴奋性。然而，大多数研究都认为 这些药物的非靶向效应是导致癫痫患者后代发生NTDS的原因。相反， 抗癫痫药物对胚胎神经兴奋性的影响大多尚不清楚，因为 普遍认为，神经活动在神经板阶段并不明显。相比之下，我们最近发表的研究 证明谷氨酸信号存在于折叠神经板中，是神经管所必需的。 队形。直接或通过孵化非洲爪哇胚胎来下调谷氨酸信号转导 抗癫痫药物丙戊酸会导致NTDS。在这项研究中，我们将发现其分子机制。 神经管形成过程中的神经递质信号。挑战主流观点，我们假设 神经板细胞囊泡释放谷氨酸是神经管形成所必需的。释放谷氨酸 在神经板细胞中诱导钙瞬变，控制调节神经细胞周期的表达和功能 像Sox2这样的蛋白质，它是调节神经干细胞更新、增殖的关键转录因子 以及神经发生，取决于其表达水平和翻译后修饰。通过使用状态- -ART成像和分子方法，我们将发现分子机制和时空 神经管形成过程中谷氨酸释放和信号传递的研究概况。我们将识别下游分子 谷氨酸释放控制神经板细胞增殖，其作用机制及对神经板细胞的影响 神经管的形成。我们将研究谷氨酸信号在Sox2表达调控中的作用 并在神经板折叠过程中发挥作用。本研究提出了一种新的范式转换模型，在该模型中 神经递质信号在神经板阶段发挥作用，对神经管的形成至关重要。 从这项研究中获得的机械论知识的意义是基于它将对 NTDS领域和对神经干细胞周期进程调控的分子理解， 这反过来将与脑瘤、脑和脊髓损伤、神经再生的研究相关。 神经退行性和神经发育障碍。这项研究，通过推进我们对机械的理解 神经活动驱动的神经管形成的研究将改善癫痫孕妇的预防措施。

Project summary One of the first steps in nervous system development consists in the folding of the neural plate and closure of the neural tube to originate the brain and spinal cord. Failure of neural tube formation leads to neural tube defects (NTDs), which are one of the most common serious birth defects. The causes of NTDs are multiple and both genetic and environmental factors have been identified. Among these factors, the use of antiepileptic drugs during pregnancy increases the incidence of NTDs by unknown mechanisms. In the mature nervous system, antiepileptic drugs decrease excitability by targeting diverse effectors. However, most studies have argued that off-target effects of these drugs are responsible for inducing NTDs in epileptic patients’ offspring. Instead, the effect of antiepileptic drugs on embryonic neural excitability remained mostly unexplored because of the prevailing view that neural activity is not apparent at neural plate stages. In contrast, our recently published study demonstrates that glutamate signaling is present in the folding neural plate and is necessary for neural tube formation. Downregulating glutamate signaling directly or by incubating Xenopus laevis embryos with the antiepileptic drug valproic acid causes NTDs. In this study we will discover the molecular mechanisms of neurotransmitter signaling during neural tube formation. Challenging the prevailing view, we hypothesize that vesicular glutamate release from neural plate cells is necessary for neural tube formation. Released glutamate elicits calcium transients in neural plate cells that control expression and function of regulatory neural cell cycle proteins like Sox2, which is a pivotal transcription factor for modulating neural stem cell renewal, proliferation and neurogenesis, depending on its level of expression and posttranslational modifications. By using state-of- the-art imaging and molecular approaches, we will discover the molecular mechanisms and spatiotemporal profile of glutamate release and signaling during neural tube formation. We will identify downstream molecules to glutamate release that control neural plate cell proliferation, their mechanisms of action and impact in the formation of the neural tube. We will examine the role of glutamate signaling on the regulation of Sox2 expression and function during neural plate folding. This study proposes a novel paradigm-shifting model in which neurotransmitter signaling is functional at neural plate stages and is crucial for the formation of the neural tube. The significance of the mechanistic knowledge gained form this study is based on the contribution it will make to the field of NTDs and to the molecular understanding of the regulation of neural stem cell cycle progression, which in turn will be relevant to research on brain tumors, brain and spinal cord injuries, neurogenesis in neurodegenerative and neurodevelopmental disorders. This study, by advancing our mechanistic understanding of neural activity-driven neural tube formation will improve preventative measures for epileptic pregnant women.