Genetic Mechanisms of Hindbrain Segmentation

描述（由申请人提供）：组织之间或组织内部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分开，使它们能够遵循独立的发育程序，尽管它们离得很近。此外，边界可以形成重要的组织中心，形成相邻细胞的模式。在发育中的脊椎动物中枢神经系统中，边界在明显均匀的神经上皮中形成，将随后获得不同组织学和功能特性的脑区域分开。特别是在后脑中，菱形球之间形成边界，沿着主体轴产生一系列7段。尽管边界在动物发育中具有根本的重要性，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，隔室边界已经吸引了研究人员几十年，但介导边界形成的实际分子直到最近才开始被阐明。这项研究的长期目标是了解脊椎动物后脑发育过程中菱形球边界形成和维持的细胞和分子基础。我们了解到，一个明显的发育边界的出现涉及两个步骤：首先，远程信号建立了具有不同区域特征但分散边界的广泛域，其次，这些域边缘的细胞之间的精细相互作用导致边界的锐化。在本提案的目标1和2中，我们通过研究两个平行过程来研究菱形球边界锐化的机制：细胞分选，即在形成边界的“错误”一侧的细胞移动到“正确”一侧，以及细胞可塑性，即在“错误”一侧的细胞改变其身份以匹配其周围环境。目的1探讨了细胞分选的机制，并验证了分选是在两种平行影响下发生的假设：菱形球边界上不同细胞之间的细胞间排斥，以及菱形球内相似细胞之间的细胞间粘附。目的2解决可塑性的机制。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.