DIVERSITY SUPPLEMENT TO DEVELOPMENTAL ORIGINS AND HOMEOSTATIC MECHANISMS UNDERLYING ADULT PHENOTYPES

项目摘要 家长奖。成人形式的起源和维持的基本机制，以及自然发生的变异， 成年人的行为，仍然知之甚少。这项研究计划旨在阐明基因活动是如何 通过细胞行为转化为成年阶段的特定形态结果。此类信息 将有助于理解胚胎后发育所必需的模式和形态发生机制， opment，与人类遗传疾病，出生缺陷，衰老和再生医学有关。为这些 努力，这项工作使用斑马鱼的色素沉着，它的近亲属Danio，更遥远的是， 晚期硬骨鱼这些动物和其他脊椎动物的色素细胞起源于胚胎神经嵴 这些细胞也有助于各种其他组织和器官，包括大多数周围神经系统。 系统和颅面骨骼。神经嵴衍生谱系的缺陷一般，色素细胞特异性- 通常与许多遗传性病理以及癌症（包括黑色素瘤）有关。期间 正常发育，色素细胞直接来自神经嵴细胞或间接通过 胚胎后干细胞中间体在胚胎发育过程中组织成高度定型的，主要是二维的模式。 透明的皮肤随着表型的发展，很容易观察到图案形成过程中的细胞行为， 遗传机制是通过突变分析和其他方法，无论是在条纹斑马鱼， 和其他有着非常不同的成年模式的物种这里描述的工作建立在以前的努力， 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， ogy和behavioral行为assays测定.未来几年的目标是阐明：（i）色素细胞 在发育过程中，祖细胞被指定为不同的色素细胞类型，以及细胞的多样性 类型已经实现了进化;（ii）遗传和细胞机制的自组织相互作用， 色素细胞之间的相互作用是必不可少的模式形成，以及这些相互作用和许可 因素已经改变，以产生物种之间的替代模式状态;（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时的作用， lishing模式，以及这些信息如何有助于跨物种的定性不同类型的模式。 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，在两个发展。 时间和进化时间。所揭示的一般原则可能适用于广泛的特征 这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， 来自组织环境的形成。 补充申请。初步研究旨在开始回答一些有关甲状腺的基本问题 激素活动在成人色素模式的形成，与揭示TH效应的机制的目标， 在细胞和转录水平的影响，同时提供了一个毕业实习生新的技能和专业发展， 开始他的论文研究和追求NRSA F31个人奖学金的机会。 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