DEVELOPMENTAL ORIGINS AND HOMEOSTATIC MECHANISMS UNDERLYING ADULT PHENOTYPES

项目摘要 成体形态的起源和维持以及成体中自然发生的变异的机制 形式，仍然知之甚少。这里描述的研究计划旨在阐明基因活动如何 通过细胞行为转化为成年阶段的特定形态结果。这样的知识- 边缘将提供深入了解胚胎后图案和形态发生的基本方面。它还将 在先天畸形、衰老、癌症和再生等领域对人类健康产生影响 药该计划侧重于斑马鱼及其亲属的成年色素沉着。色素细胞谱系 脊椎动物起源于胚胎的神经嵴，依靠精确的机制来分离命运， 在广泛形态发生的背景下调节分化，特别是迁移。除了分享 这些特征与其他神经嵴衍生物，成人色素细胞是有趣的，因为他们组织 自然发生的模式的多样化阵列;因为它们来自潜在的祖先-所以可以 更普遍地提供了对干细胞生物学的见解;并且因为这些谱系引起黑色素瘤， 这代表着成年人体内平衡和生长控制的严重失败，并带来致命的后果。工作 这里提出的将建立在我们先前的努力，即识别具有不同基因的色素细胞的不同谱系的艾德， 遗传和内分泌的要求，以及我们发现的几种类型的相互作用，色素细胞 需要建立，实施和维持物种特异性形式的成人模式的类。我们 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， 斑马鱼成体条纹发育过程中对甲状腺激素的不同依赖性;（ii） 哪些色素细胞谱系，特别是潜伏干细胞，在成人体内平衡过程中受到调节， 这些过程中的缺陷如何导致黑色素瘤的易感性和进展;以及（iii）以前如何 未经研究的色素细胞命运受到调节，色素细胞被组织起来，以产生物种特异性模式 变体。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 询问基因活动的方法，我们不仅将利用斑马鱼的条纹， 斑马鱼近亲的多样性，同样的方法很容易应用。我们共同努力， 提供了新的见解的遗传和细胞基础的成人形式的这种神经嵴衍生性状， 基本和翻译的含义。 ! 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