The reverse hingepoint: a novel, essential feature of neurulation

反向铰点：神经系统的一个新颖的基本特征

• 批准号: 10217527
• 负责人: Rachel Melissa Brewster
• 金额: $ 22.59万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE COUNTY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10217527
• 关键词: Actomyosin; Alleles; Anterior; Apical; Basal Cell; Basal lamina; Biological Models; Candidate Disease Gene; Cell Shape; Cells; Cephalic; Congenital Abnormality; Cytoskeleton; Data; Defect; Development; Epithelial; F-actin-binding proteins; Frequencies; Genes; Geometry; Human; Image; Impairment; Integrins; Knowledge; Lateral; Link; Mechanics; Medial; Mediating; Modeling; Molecular; Mutation; Myosin ATPase; Neural Fold; Neural Tube Closure; Neural Tube Defects; Neural Tube Development; Neural tube; Patients; Process; Prosencephalon; Scanning; Shapes; Side; Specific qualifier value; Structural Congenital Anomalies; Structure; Surface; System; Telencephalon; Testing; Time; Tissues; Validation; Variant; Work; Zebrafish; base; blebbistatin; causal variant; cohort; constriction; emx2 protein; gain of function; genetic risk factor; loss of function; mutant; neural plate; novel; progenitor; recruit; rho; transcription factor

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.

摘要 神经管缺陷(NTD)是第二种最常见的结构性出生缺陷，尽管其发病率很高 频率，形成神经管的基本机制仍然知之甚少。在.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。 铰点，使神经折叠紧密对位，并导致它们的融合，从而完成 神经管的形成。内侧铰点的发现对这一领域至关重要，因为它不仅 为扁平神经板最初如何弯曲成V形提供了一个机械解释，但它 也导致在NTDS患者中发现了几个致病突变。与之相对的是 神经板的中心区域，该上皮层的边缘以相反的方向折叠 塑造神经皱褶。顺理成章地，这一过程将涉及细胞的反向变化 形状(反向铰点或RHP)和初步数据证实了这一预测，但分子 对这一过程缺乏了解。我们建议检验RHP形成的中心假设 是由收缩机械重新聚集到神经皱折细胞的基极，在 前脑特异转录因子传递的空间信息。在目标1中，我们将调查 塑造RHP细胞的分子机制，在目标2中，我们将研究区域认同如何 由形成RHP的前脑特异转录因子物种传递。 在完成拟议的研究后，我们将了解关键的细胞和分子机制。 这调节了RHP的形成，并填补了我们对神经形成基础知识的一个重要空白。 这些研究将为识别新的NTD遗传风险因素铺平道路，提供一种 候选基因中人类变异功能验证的发展框架 Emx2和整合素b1。