DEVELOPMENTAL ORIGINS AND HOMEOSTATIC MECHANISMS UNDERLYING ADULT PHENOTYPES

项目总结 成体形态起源和维持的机制，以及成体的自然变异 形式，仍然鲜为人知。这里描述的研究计划试图阐明基因活动是如何 在成虫阶段通过细胞行为转化为特殊的fic形态结果。如此的了解- EDGE将提供对胚胎后模式和形态发生的基本方面的见解。它还将 在先天畸形、衰老、癌症和再生领域对人类健康产生相关影响 医药。本节目的重点是斑马fish及其近亲的成体色素沉着。色素细胞谱系在 脊椎动物起源于胚胎的神经脊，依靠精确的机制来区分命运和 在广泛的形态发生，特别是迁移的背景下调节分化。除了分享 这些特征与其他神经脊衍生物一样，成体色素细胞很有趣，因为它们组织 形成一系列不同的自然发生的模式；因为它们起源于潜在的祖先--因此也可以 提供对干细胞生物学的更广泛的见解；因为这些谱系会导致黑色素瘤， 代表着成人动态平衡和生长控制的严重失败，并带来致命的后果。这项工作 在此提出的建议将建立在我们先前的工作的基础上，即识别具有不同GE-fi的不同的色素细胞谱系。 蛋白质和内分泌需求，以及我们发现的几种类型的色素细胞之间的相互作用 建立、实施和维护种属fic形式的成虫模式所需的类。我们的 未来几年的目标是阐明：(I)色素细胞相互作用的遗传和细胞机制以及 斑马fish成体条纹发育过程中对甲状腺激素的不同依赖；(Ii) 哪些色素细胞系，特别是潜伏干细胞，在成体动态平衡期间受到调节，以及 这些过程中的缺陷如何促进黑色素瘤的易感性和进展；以及(Iii)以前是如何 未被研究的色素细胞命运受到调节，色素细胞被组织起来，以产生物种特有的fic模式。 变种。为了达到这些目的，我们将使用一套方法，包括最先进的成像和现代 方法，我们将不仅利用斑马fish的条带，而且还将利用 斑马fish近亲的多样性，同样的方法也很容易应用于这些斑马。我们的共同努力将 提供了对这种神经脊衍生特征的成人形式的遗传和细胞基础的新见解， 既有基本含义，也有翻译含义。 1

PROJECT SUMMARY Mechanisms underlying the origin and maintenance of adult form, and naturally occurring variation in adult form, remain poorly understood. The research program described here seeks to elucidate how gene activities are translated through cellular behaviors into specific morphological outcomes at adult stages. Such knowl- edge will provide insights into essential aspects of post-embryonic patterning and morphogenesis. It will also have impacts relevant to human health in the realms of congenital deformity, aging, cancer and regenerative medicine. This program focuses on adult pigmentation of zebrafish and its relatives. Pigment cell lineages in vertebrates originate in the embryonic neural crest and depend on precise mechanisms to segregate fate and regulate differentiation in a context of extensive morphogenesis, and particularly migration. Besides sharing these features with other neural crest derivatives, adult pigment cells are interesting because they organize into a diverse array of naturally occurring patterns; because they arise from latent progenitors—and so can provide insights into stem cells biology more generally; and because these lineages give rise to melanoma, representing a profound failure of adult homeostasis and growth control with deadly consequences. The work proposed here will build on our prior efforts that identified distinct lineages of pigment cells having distinct ge- netic and endocrine requirements, as well as our discovery of several types of interactions among pigment cell classes that are needed to establish, implement, and maintain species-specific forms of adult pattern. Our goals in the coming years are to elucidate: (i) genetic and cellular mechanisms of pigment cell interactions and differential dependencies on thyroid hormone during adult stripe development in zebrafish; (ii) the ways in which pigment cell lineages, and particularly latent stem cells, are regulated during adult homeostasis, and how defects in these processes contribute to melanoma susceptibility and progression; and (iii) how previously unstudied pigment cell fates are regulated, and pigment cells organized, to generate species-specific pattern variants. Towards these ends we will use a suite of approaches, including state of the art imaging and modern methods of interrogating gene activities, and we will exploit not only stripes of zebrafish but also the pattern diversity of close zebrafish relatives, to which the same methods are readily applied. Together our efforts will provide novel insights into the genetic and cellular bases for adult forms of this neural crest derived trait, with implications both basic and translational. !1