Melanocyte boundary interactions in development and neoplasia

描述(由研究人员提供)：细胞和组织之间边界的建立是每个动物胚胎模式形成的关键特征。随着器官发生和生长在胚胎后期发育中继续进行，这些相同的界限必须保持，并建立新的界限。在成年以后，细胞和组织边界的维持对于正常的内稳态是必不可少的。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病、癌症和再生环境产生了深远的影响，在这些疾病中，边界约束消失了，而在再生环境中，边界必须重新形成。该项目的目标是了解胚胎后脊椎动物发育过程中潜在的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斑马鱼边界形成的例子，即斑马鱼成体色素条纹的发育和维持。以前的研究表明，不同类别的色素细胞之间的相互作用对于正常条纹的发育是必不可少的，尽管涉及的基因和细胞行为尚未阐明。在拟议的目标1中，时间推移成像将用于显示条纹发育和再生过程中细胞与细胞的相互作用，并检验涉及直接、短距离和远程接触的假设。目标2将测试以前分离的和具有边界缺陷表型的突变的新基因的功能。除了正常发育外，这些研究还将扩展到对黑色素瘤细胞的行为进行成像，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，测试一类新的色素细胞在边界形成中的功能，以及候选遗传途径在调节这些影响方面的作用。最后，目标4将通过对候选途径的分析以及对不同阶段和遗传背景的特定色素细胞群体之间的整个转录本的比较，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广泛的边界形成机制的逻辑提供有价值的新见解。 公共卫生相关性：细胞和组织边界的建立和维持对正常发育至关重要。反过来，发现这些过程背后的机制将对人类健康和疾病以及刺激创伤后组织再生的努力产生重要影响。这项建议中的这些研究集中在色素细胞上，在人类中，色素细胞与包括黑色素瘤在内的各种疾病有关。我们的研究将揭示在发育过程中负责形成和维持边界的基因和细胞行为，以及这些机制如何与肿瘤状态相互作用。

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.