Developmental origins and homeostatic mechanisms underlying adult phenotypes

成人表型的发育起源和稳态机制

• 批准号: 10725034
• 负责人: DAVID M PARICHY
• 金额: $ 8.07万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10725034
• 关键词: Adult; Aging; Animals; Behavioral Assay; Cells; Comparative Biology; Congenital Abnormality; Defect; Development; Distant; Elements; Embryo; Embryonic Development; Environment; Genes; Genetic; Genetic Diseases; Genomics; Goals; Homeostasis; Human Genetics; Inherited; Location; Maintenance; Malignant Neoplasms; Morphology; Mutation Analysis; Neural Crest; Neural Crest Cell; Organ; Outcome; Pathology; Pattern; Pattern Formation; Peripheral Nervous System; Phenotype; Pigmentation physiologic function; Pigments; Postembryonic; Public Health; Regenerative Medicine; Research; Role; Skeleton; Skin; Specific qualifier value; Stereotyping; Time; Tissues; Translating; Variant; Vertebrates; Work; Zebrafish; cell behavior; cell type; craniofacial; experimental study; genetic analysis; high resolution imaging; insight; melanoma; novel; permissiveness; postembryonic stem cell; programs; repaired; self organization; stem cells; teleost fish; trait; two-dimensional

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

项目概要 成人形态起源和维持的机制，以及成人自然发生的变异 该研究项目旨在阐明基因活性是如何转化的。 通过细胞行为转化为成年阶段的特定形态结果。 有助于理解胚胎后发育所必需的模式和形态发生机制， 与人类遗传疾病、出生缺陷、衰老和再生医学相关。 该作品使用了斑马鱼、其近亲斑马鱼以及关系较远的硬骨鱼的色素沉着 这些动物和其他脊椎动物的色素细胞也来自胚胎神经嵴细胞。 有助于多种其他组织和器官，包括大部分周围神经系统和 颅面骨骼的缺陷一般来说是神经嵴衍生的谱系，特别是色素细胞的缺陷。 与许多遗传性疾病以及癌症有关，包括正常发育过程中的黑色素瘤。 色素细胞，直接由神经嵴细胞产生或通过胚胎干细胞间接产生 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，模式形成过程中的细胞行为很容易观察到 可以通过突变分析和其他方法获得，无论是在条纹斑马鱼还是其他动物中 这里描述的工作建立在该计划先前的努力的基础上，并且 采用一种异常综合的方法来理解模式和模式变化，结合操作 实验、遗传分析、高分辨率成像、尖端基因组学、比较生物学和 Be- 未来几年的目标是阐明：（i）色素细胞祖细胞的机制。 在发育过程中针对不同的色素细胞类型进行了指定，以及细胞类型的多样化是如何发生的 (ii) 自组织相互作用的遗传和细胞机制 对于图案形成至关重要的色素细胞，以及这些相互作用和许可因素如何发挥作用 改变以在物种之间产生替代模式状态；（iii）位置信息在组织中的作用 苏环境设置对于建立模式至关重要的离散模式元素的位置， 以及这些信息如何促成跨物种的不同类型的定性模式。 将为发育和发育过程中的模式发育和细胞类型多样化提供新的见解 所发现的一般原则可能适用于依赖于进化时间的广泛特征。 不同程度的细胞类型多样化、自组织细胞相互作用以及衍生的位置信息 来自组织环境。 1