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。这项研究计划旨在阐明基因活动是如何翻译的， 通过细胞行为转化为成年阶段的特定形态结果。这样的信息将被... 对理解胚胎后发育所必需的模式和形态发生机制的贡献， 与人类遗传疾病、出生缺陷、衰老和再生医学有关。对于这些努力， 这项工作使用了斑马鱼的色素，斑马鱼是它在Danio属中的近亲，也是更远的硬骨鱼 鱼。这些动物和其他脊椎动物中的色素细胞来自胚胎神经嵴细胞， 有助于多种其他组织和器官，包括大多数周围神经系统， 颅面骨骼神经嵴衍生谱系的缺陷，特别是色素细胞的缺陷，如- 与许多遗传性疾病以及癌症，包括黑色素瘤有关。在正常发展过程中， 色素细胞直接起源于神经嵴细胞或间接起源于胚后干细胞 细胞中间体在透明皮肤中组织成高度定型的、主要是二维的图案。 随着表型的发展和遗传机制的发展，很容易观察到图案形成期间的细胞行为。 可以通过突变分析和其他方法获得，无论是在条纹斑马鱼和其他 有非常不同的成年模式的物种。这里描述的工作建立在本计划的前期工作基础上， 采取一种不同寻常的综合方法来理解模式和模式变化，结合操纵 实验，遗传分析，高分辨率成像，尖端基因组学，比较生物学和生物学， 口服测定。未来几年的目标是阐明：（i）色素细胞祖细胞 艾德在发育过程中对不同的色素细胞类型有特异性，以及细胞类型的多样性是如何被 （二）遗传和细胞机制之间的自组织相互作用 色素细胞是必不可少的模式形成，以及如何这些相互作用和许可因素， 改变以产生物种之间的替代模式状态;（iii）位置信息在TIS中的作用， 利用环境来设置对建立图案至关重要的离散图案元素的位置， 以及这些信息是如何在物种之间形成不同类型的模式的。这些努力 将提供新的见解模式的发展和细胞类型的多样性，在发展和 进化时间所揭示的一般原则可能适用于广泛的性状，这些性状取决于 不同程度的细胞类型多样性，自组织细胞相互作用和位置信息 从组织环境中分离出来 1

PROJECT SUMMARY Mechanisms underlying the origin and maintenance of adult form, and naturally occurring variation in adult form, remain poorly understood. This research program seeks to elucidate how gene activities are translated through cellular behaviors into specific morphological outcomes at adult stages. Such information will con- tribute to understanding patterning and morphogenetic mechanisms essential for postembryonic development, with relevance to human genetic disease, birth defects, aging and regenerative medicine. For these efforts, the work uses pigmentation of zebrafish, its close relatives in the genus Danio, and more distantly related teleost fishes. Pigment cells in these animals and other vertebrates arise from embryonic neural crest cells that also contribute to a wide variety of other tissues and organs, including most of the peripheral nervous system and craniofacial skeleton. Defects in neural crest derived lineages generally, and pigment cells specifically, are as- sociated with numerous hereditary pathologies as well as cancers, including melanoma. During normal devel- opment, pigment cells that arise either directly from neural crest cells or indirectly through postembryonic stem cell intermediates organize into highly stereotyped, largely two dimensional patterns in the transparent skin. Cell behaviors during pattern formation are readily observed as phenotypes develop, and genetic mechanisms are accessible through mutational analyses and other approaches, both in striped zebrafish and in other species having very different adult patterns. The work described here builds on prior effort in this program, and takes an unusually integrative approach to understand pattern and pattern variation, combining manipulative experiments, genetic analysis, high resolution imaging, cutting edge genomics, comparative biology and be- havioral assays. Goals in the coming years are to elucidate: (i) mechanisms by which pigment cell progenitors are specified for different pigment cell types during development, and how diversification of cell types has been achieved evolutionarily; (ii) genetic and cellular mechanisms underlying self-organizing interactions among pigment cells that are essential for pattern formation, and how these interactions and permissive factors have changed to generate alternative pattern states among species; (iii) the roles of positional information in the tis- sue environment in setting the location of discrete pattern elements that are essential for establishing pattern, and how such information contributes to qualitatively different types of pattern across species. These efforts will provide novel insights into pattern development and cell type diversification over both developmental and evolutionary time. General principles uncovered will likely be applicable to a wide range of traits that depend to varying degrees cell type diversification, self-organizing cellular interactions, and positional information derived from tissue environments. 1