Regulation of cell polarity during neurulation

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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.