Genetic Mechanisms of Hindbrain Segmentation

描述(由申请人提供)：组织之间或组织内边界的形成是动物发育的一个基本方面。边界的作用是将具有不同身份的细胞群体分开，使它们能够遵循独立的发育程序，尽管它们非常接近。此外，边界可以形成重要的组织中心，使相邻的单元格式化。在发育中的脊椎动物中枢神经系统中，边界在表面上均一的神经上皮中形成，分隔大脑区域，这些区域随后获得不同的组织和功能特性。特别是在后脑，菱形脑之间的边界形成，沿着主体轴产生一系列的7个节段。尽管边界在动物发育中具有基本的重要性，但令人惊讶的是，人们对控制边界形成的分子和机制知之甚少。即使在果蝇中，隔室边界几十年来一直令研究人员感兴趣，但调节边界形成的实际分子直到最近才开始被阐明。这项拟议研究的长期目标是了解脊椎动物后脑发育过程中菱形脑边界形成和维持的细胞和分子基础。我们理解，尖锐的发育边界的出现包括两个步骤：第一，远程信号建立具有不同区域特征但分散的边界的广泛区域，第二，这些区域边缘的细胞之间的精细相互作用导致边界变得尖锐。在这项建议的目标1和2中，我们通过研究两个平行的过程来研究菱形边界锐化的机制：细胞分类，即形成边界的“错误”侧的细胞移动到“正确”侧，以及细胞可塑性，即“错误”侧的细胞改变其身份以匹配其周围环境。目的1探讨细胞分选的机制，并检验细胞分选是在两种平行影响下发生的假说：菱形边界处不同细胞之间的细胞-细胞排斥和菱形内相似细胞之间的细胞-细胞黏附。目标2阐述了可塑性的机制。最后，在目标3中，我们考虑了远程信号相互作用以指定特定后脑边界位置的机制。

DESCRIPTION (provided by applicant): The formation of boundaries between or within tissues is a fundamental aspect of animal development. Boundaries function to separate populations of cells with different identities, allowing them to follow independent developmental programs in spite of their close proximity. Additionally, boundaries can form important organizing centers that pattern adjacent cells. In the developing vertebrate central nervous system, boundaries form in an apparently homogeneous neuroepithelium, separating brain regions that subsequently acquire distinct histological and functional properties. In the hindbrain in particular, boundaries form between the rhombomeres, producing a series of 7 segments along the main body axis. In spite of the fundamental importance of boundaries in animal development, surprisingly little is known about the molecules and mechanisms that control boundary formation. Even in Drosophila, where compartment boundaries have intrigued researchers for decades, the actual molecules that mediate boundary formation have only recently begun to be elucidated. The long-term goal of the proposed research is to understand the cellular and molecular basis of rhombomere boundary formation and maintenance during vertebrate hindbrain development. We understand that the appearance of a sharp developmental boundary involves 2 steps: first, long-range signals establish broad domains with distinct regional identities but diffuse boundaries, and secondly fine-scale interactions between cells at the edges of these domains result in the sharpening of the boundaries. In Aims 1 and 2 of this proposal we investigate the mechanisms underlying rhombomere boundary sharpening by studying two parallel processes: cell sorting, whereby cells on the "wrong" side of a forming boundary move to the "right" side, and cell plasticity, whereby cells on the "wrong" side change their identity to match that of their surroundings. Aim 1 addresses the mechanism of cell sorting, and tests the hypothesis that sorting occurs in response to 2 parallel influences: cell-cell repulsion between unlike cells at rhombomere boundaries, and cell-cell adhesion between like cells within rhombomeres. Aim 2 addresses the mechanism of plasticity. Finally, in Aim 3, we consider the mechanism by which long-range signals interact to specify the positions of specific hindbrain boundaries.