Regulation of cell polarity during neurulation

描述（由申请人提供）：神经形成被定义为一系列形态发生运动，导致神经管的形成，神经管是一种背侧中空的神经索，构成整个成人中枢神经系统的雏形。在鸡和小鼠胚胎的后部区域，神经形成涉及间充质细胞凝结形成髓索。这个过程（称为次级神经发育）在细胞和形态学水平上类似于斑马鱼的神经发育模式。尽管经过几十年的研究，这种类型的神经调节的遗传基础仍然知之甚少。斑马鱼神经管的形成取决于细胞正确极化的能力。极性首先表现为定向膜突起的延伸，驱动神经细胞向背中线收敛。一旦这些间充质细胞合并成一个神经杆，它们转变成上皮结构，建立一个明确定义的顶基轴。该建议的总体目标是了解在神经发育过程中如何调节细胞极性，以及这种极性的破坏如何扰乱形成神经管和神经细胞结构的形态发生运动。在目标1中，我们提出定位克隆和表征linguini，一个适当的神经收敛所需的位点。我们假设lin稳定了神经细胞中的微管，从而使细胞运动极化。在目的2中，我们将研究Par3在上皮化过程中定位顶皮层中心体中的新作用。我们将鉴定中心体定位所需的Par3相互作用蛋白，并确定Par3是否以微管依赖的方式调节这一过程。在目标3中，我们探讨了中线组织在提供一个假定的化学吸引线索，指导细胞在神经收敛过程中的作用。这些细胞和分子的研究将最终增加我们对人类神经管出生缺陷的病因学的理解。

DESCRIPTION (provided by applicant): Neurulation is defined as a series of morphogenetic movements that result in the formation of the neural tube, a dorsal hollow nerve cord that constitutes the rudiment of the entire adult central nervous system. In the posterior region of the chick and mouse embryo, neurulation involves the condensation of mesenchymal cells to form a medullary chord. This process (termed secondary neurulation) resembles, at a cellular and morphological level, the mode of neurulation in the zebrafish. Despite decades of research, the genetic basis for this type of neurulation remains poorly understood. Formation of the neural tube in the zebrafish is dependent on the ability of cells to polarize properly. Polarity is first manifested by the extension of directional membrane protrusions that drive neural cell convergence towards the dorsal midline. Once these mesenchymal cells have coalesced into a neural rod, they transition into an epithelial configuration, establishing a clearly defined apico-basal axis. The overall goal of this proposal is to understand how cell polarity is regulated during neurulation and how disruption of this polarity perturbs both the morphogenetic movements that shape the neural tube and neural cytoarchitecture. In aim 1, we propose to positionally clone and characterize linguini, a locus required for proper neural convergence. We hypothesize that lin stabilizes microtubules in neural cells, thereby polarizing cell movement. In aim 2, we will investigate a novel role for Par3 in positioning the centrosome at the apical cortex during epithelialization. We will identify Par3-interacting proteins required for centrosome positioning and determine whether Par3 regulates this process in a microtubule-dependent manner. In aim 3, we explore the role of midline tissues in providing a putative chemoattractive cue that guides cells during neural convergence. These cellular and molecular studies will ultimately increase our understanding of the etiology underlying human neural tube birth defects. PUBLIC HEALTH RELEVANCE: Neurulation is defined as a series of morphogenetic movements that result in the formation of the neural tube, a dorsal hollow nerve cord that constitutes the rudiment of the entire adult central nervous system. Knowledge of the mechanisms of secondary neurulation is essential, given the high incidence of human posterior spinal cord malformations. However, despite decades of research, the cellular and genetic basis for this type of neurulation remains poorly understood. The goal of this research proposal is to use the various genetic tools and labeling techniques available in the zebrafish, to investigate the mechanisms underlying secondary neurulation. These studies will ultimately increase our understanding of how neurulation is orchestrated and provide a molecular basis for exploring the etiology of posterior neural tube defects in humans.