DIVERSITY SUPPLEMENT TO DEVELOPMENTAL ORIGINS AND HOMEOSTATIC MECHANISMS UNDERLYING ADULT PHENOTYPES

项目总结 家长奖。成体的起源和维持的机制，以及自然发生的变异- 在成人形式下，仍然知之甚少。这项研究计划试图阐明基因活动是如何 在成体阶段通过细胞行为转化为特殊的fic形态结果。这样的信息 将有助于理解胚胎后发育所必需的图案化和形态发生机制 与人类遗传病、出生缺陷、衰老和再生医学有关。为了这些 经过努力，这项工作使用了斑马fish，它是丹尼奥属的近亲，并在更远的地方重新 迟来的硬骨鱼fi她。这些动物和其他脊椎动物中的色素细胞来自胚胎神经脊 细胞也对各种各样的其他组织和器官做出贡献，包括大多数周围神经 系统和头面部骨骼。神经脊源性谱系的缺陷，以及特定的色素细胞fi- CALY与许多遗传性疾病以及包括黑色素瘤在内的癌症有关。在.期间 正常发育，色素细胞直接来自神经脊细胞或间接通过 胚胎后干细胞中间体组织成高度定型的，主要是二维模式 透明的皮肤。随着表型的发展，很容易观察到模式形成期间的细胞行为，并且Ge-Ge-1。 在条纹斑马fish中，通过突变分析和其他方法可以获得磁机制。 在其他物种中也有非常不同的成虫模式。这里描述的工作建立在此之前的工作基础上 程序，并采取了一种不同寻常的综合方法来理解模式和模式变异，结合 操作实验，遗传分析，高分辨率成像，尖端基因组学，比较生物学- 生物学和行为分析。未来几年的目标是阐明：(I)色素细胞 前体细胞在发育过程中针对不同的色素细胞类型，以及细胞阳离子的多样性。 类型是通过进化获得的；(Ii)自组织相互作用的遗传和细胞机制。 色素细胞之间的相互作用是形成图案所必需的，以及这些相互作用和允许 因素发生了变化，以产生物种之间的替代格局状态；(Iii)位置信息的作用-- 在组织环境中设置离散图案元素的位置，这些离散图案元素对于建立- Lish模式，以及这些信息如何有助于不同物种的定性不同类型的模式。 这些努力将为模式发展和细胞类型多样化提供新的见解，在这两个发展过程中。 运筹学和进化论。已发现的一般原则可能适用于广泛的特征 这在不同程度上依赖于细胞类型的多样性、自组织的细胞相互作用和位置上的fi。 来自组织环境的形成。 补充请求。试点研究旨在开始回答一些与甲状腺有关的基本问题 成虫花纹形成过程中的激素活性，目的在于揭示黄粉病的作用机制。 在细胞和转录水平上的效果，同时为毕业生实习生提供新的技能和专业发展- 开始他的论文研究，并获得NRSA F31个人奖学金。 1

PROJECT SUMMARY Parent award. Mechanisms underlying the origin and maintenance of adult form, and naturally occurring varia- tion 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 contribute to understanding patterning and morphogenetic mechanisms essential for postembryonic devel- opment, 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 re- lated 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 specifi- cally, are associated with numerous hereditary pathologies as well as cancers, including melanoma. During normal development, 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 ge- netic 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 biol- ogy and behavioral 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 interac- tions 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 informa- tion in the tissue environment in setting the location of discrete pattern elements that are essential for estab- lishing 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 devel- opmental 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 in- formation derived from tissue environments. Supplement request. Pilot research is designed to begin answering some basic questions pertaining to thyroid hormone activities during adult pigment pattern formation, with the goal of uncovering mechanisms of TH ef- fects at cellular and transcriptomic levels, while providing a graduate trainee new skills and professional devel- opment towards initiating his dissertation research and pursuing an NRSA F31 individual fellowship. 1