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

项目总结 成体形态起源和维持的机制，以及成体的自然变异 形式，仍然鲜为人知。这项研究计划试图阐明基因活动是如何转化的。 通过细胞行为转化成特定的fic成虫阶段的形态结果。该等资料将包括- 为了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。在这些努力中， 工作使用斑马fish，它在danio属中的近亲，以及更远的近亲硬骨鱼的色素沉着。 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，这些细胞也 有助于广泛的其他组织和器官，包括大多数周围神经系统和 头面部骨骼。神经脊来源的谱系的缺陷，特别是色素细胞fi的缺陷，通常是- 与许多遗传性疾病以及包括黑色素瘤在内的癌症有关。在正常发展过程中- 直接从神经脊细胞或通过胚胎后干细胞间接产生的色素细胞 在透明的皮肤中，细胞中间体组织成高度定型的、主要是二维的图案。 随着表型的发展和遗传机制的发展，很容易观察到模式形成期间的细胞行为 可通过突变分析和其他方法在条纹斑马fish和其他 具有非常不同的成虫模式的物种。这里描述的工作建立在该计划中先前的工作基础上，并且 采取了一种不同寻常的综合方法来理解模式和模式变化，结合操控 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- 行为化验。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，以及细胞类型的阳离子是如何多样化的 (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允许因素如何 改变以产生物种之间的替代模式状态；(Iii)位置信息在物种间的位置信息的作用-- 在设置建立图案所必需的离散图案元素的位置时， 以及这些信息如何促成不同物种之间的定性不同类型的模式。这些努力 将提供关于发育和细胞类型差异的模式发展和fi的新见解 进化的时间。已发现的一般原则可能适用于广泛的特征，这些特征取决于 不同程度的细胞类型fi阳离子、自组织细胞相互作用和位置信息派生 从组织环境中。 1