Melanocyte boundary interactions in development and neoplasia

描述（由研究者提供）：细胞和组织之间边界的建立是每种动物胚胎模式形成的关键特征。在胚胎后期发育过程中，随着器官发生和生长的继续，必须保持这些相同的边界，并建立新的边界。在成年后，细胞和组织边界的维持对于正常的体内平衡是必不可少的。因此，这些边界背后的机制具有基本的生物学意义。然而，这些相同的机制也对各种遗传疾病、癌症和必须重新形成边界的再生环境有着深远的影响。该项目的目标是了解胚胎后脊椎动物发育中细胞边界的遗传和细胞机制。为此，这些研究将采用一个特别容易处理的边界形成的例子，斑马鱼成年色素条纹的发育和维持。先前的研究表明，不同种类的色素细胞之间的相互作用对正常条纹的形成至关重要，尽管涉及的基因和细胞行为尚未被阐明。在拟议的目标1中，延时成像将用于可视化条纹发育和再生过程中的细胞-细胞相互作用，并测试直接，短距离和远程接触涉及的假设。目标2将测试先前分离的和突变体具有边界缺陷表型的新基因的功能。除了正常发育外，这些研究还将扩展到黑色素瘤细胞的成像行为以及这些细胞的侵袭和转移如何受到遗传背景的影响。目标3将建立在早期研究的基础上，通过测试一类新的色素细胞在边界形成中的功能，以及介导这些影响的候选遗传途径的作用。最后，Aim 4将通过分析候选途径以及比较不同阶段和遗传背景的特定色素细胞群体之间的全转录组，确定有助于条纹边界形成的新基因和途径。这些研究将为色素细胞边界形成和黑色素瘤进展的遗传学以及更普遍的边界形成机制的逻辑提供有价值的新见解。

DESCRIPTION (provided by investigator): The establishment of boundaries between cells and tissues is a critical feature of pattern forma- tion in every animal embryo. These same boundaries must be maintained and new ones established as organogenesis and growth continue during later post-embryonic development. Still later in the adult, the maintenance of cell and tissue boundaries is essential for normal homeo- stasis. The mechanisms underlying such boundaries are thus of fundamental biological significance. Yet these same mechanisms also have profound implications for a variety of genetic diseases, cancers, in which boundary constraints are lost, and regenerative contexts, in which boundaries must be formed anew. The goal of this project is to understand the genetic and cellular mechanisms underlying cellular boundaries in post-embryonic vertebrate development. To this end, these studies will employ an especially tractable example of boundary formation, the development and maintenance of adult pigment stripes in the zebrafish. Previous efforts demonstrated that interactions between different classes of pigment cells are essential for normal stripes to develop, though the genes and cell behaviors involved have yet to be elucidated. In proposed Aim 1, time-lapse imaging will be used to visualize cell-cell interactions during stripe development and regeneration, and to test the hypothesis that direct, short-range and long- range contacts are involved. Aim 2 will test functions of previously isolated and new genes for which mutants have boundary-defective phenotypes. In addition to normal development, these studies will extent to imaging the behavior of melanoma cells and how invasion and metastasis by these cells is affected by genetic background. Aim 3 will build upon earlier studies by testing a new class of pigment cell for its function in boundary formation, as well as the role of a candidate genetic pathway for mediating these effects. Finally, Aim 4 will identify new genes and pathways contributing to stripe boundary formation through the analysis of candidate pathways as well as comparisons of whole transcriptomes between defined pigment cell populations across stages and genetic backgrounds. These studies will provide valuable new insights into the genetics of pigment cell boundary formation and melanoma progression, as well as the logic of boundary forming mechanisms more generally. PUBLIC HEALTH RELEVANCE: The establishment and maintenance of cell and tissue boundaries is critical for normal development. In turn, discovering the mechanisms underlying such processes will have important implications for human health and disease, as well as efforts to stimulate tissue regeneration following traumatic injury. These studies in this proposal focus on pigment cells, which in humans are associated with a variety of disorders including melanoma. Our research will shed new light on the genes and cell behaviors responsible for the formation and maintenance of boundaries during development, and how these mechanisms interact with the neoplastic state.