The reverse hingepoint: a novel, essential feature of neurulation

摘要 神经管缺陷（NTD）是第二大常见的结构性出生缺陷，但尽管其高 虽然我们对神经管的频率、形成神经管的基本机制仍知之甚少。期间 神经形成时，神经板围绕内侧和两侧以双相方式弯曲和折叠 铰链点，使神经褶皱紧密并列，并导致其融合，完成 神经管形成内侧铰链点的发现是该领域的关键，因为它不仅 为扁平的神经板最初如何弯曲成V形提供了一个机械解释，但它 也导致了NTD患者中几种致病突变的鉴定。相对于 在神经板的中心区域，该上皮层的边缘以与神经板的边缘相反的方向折叠。 塑造神经褶皱很明显，这一过程将涉及细胞的逆转， 形状（反向铰接点或RHP）和初步数据证实了这一预测，然而， 对这个过程缺乏了解。我们建议测试中心假设，RHP的形成 是由收缩机制的募集驱动的神经褶细胞的基底极，下游 空间信息由前脑特异性转录因子传递。在目标1中，我们将研究 分子机制，形成RHP细胞，在目标2，我们将研究如何区域身份 由RHP形成的前脑特异性转录因子种类传递。 完成这些研究后，我们将了解关键的细胞和分子机制 它介导了RHP的形成，填补了我们对神经胚形成基础知识的重要空白。 这些研究将通过提供一个新的NTD遗传风险因素的识别铺平道路， 用于候选基因中人类变体的功能验证的开发框架， EMX 2和整合素B1。

Abstract Neural tube defects (NTDs) are the second most common structural birth defect, yet despite their high frequency, the fundamental mechanisms that shape the neural tube are still poorly understood. During neurulation, the neural plate bends and folds in a biphasic manner around a medial and bi-lateral hingepoints, bringing the neural folds in close apposition and leading to their fusion, which completes neural tube formation. The discovery of the medial hingepoint was pivotal to the field, as it not only provided a mechanistic explanation for how the flat neural plate initially bends into a V shape, but it also led to the identification of several causative mutations in patients with NTDs. In contrast to the central region of the neural plate, the edges of this epithelial layer fold in the opposite direction to shape the neural folds. It stands to reason that this process would involve a reverse change in cell shape (reverse hingepoint or RHP) and preliminary data confirms this prediction, however a molecular understand of this process is lacking. We propose to test the central hypothesis that RHP formation is driven by recruitment of contractile machinery to the basal pole of neural fold cells, downstream of spatial information conveyed by forebrain-specific transcription factors. In aim 1 we will investigate the molecular mechanisms that shape RHP cells and in aim 2 we will examine how regional identity conveyed by forebrain-specific transcription factors species where RHPs form. Upon completion of the proposed studies, we will understand key cellular and molecular mechanisms that mediate RHP formation and have filled an important gap in our basic knowledge of neurulation. These studies will pave the way towards identification of novel NTD genetic risk factors by providing a developmental framework for functional validation of human variants in candidate genes such as emx2 and integrin b1.