Mechanisms of vertebrate post-embryonic developmental progression

脊椎动物胚胎后发育进程的机制

• 批准号: 8733740
• 负责人: Sarah Kelly McMenamin
• 金额: $ 8.49万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-13 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8733740
• 关键词: Address; Adolescent; Adopted; Adult; Affect; Architecture; Behavior; Biology; Cell Lineage; Cell physiology; Cells; Cloning; Congenital Disorders; Defect; Development; Developmental Biology; Developmental Gene; Developmental Gene Expression Regulation; Developmental Process; Disease; Ecology; Embryo; Embryonic Development; Endocrine; Event; Exhibits; Failure; Foundations; Genes; Genetic; Genetic Screening; Goals; Health; Hormones; Human; Human Development; Impairment; Laboratory Research; Larva; Life; Mammals; Maps; Massive Parallel Sequencing; Mediator of activation protein; Methods; Modeling; Modification; Morphogenesis; Morphology; Mutation; Neonatal; Organ; Organism; Pathway interactions; Perinatal; Phenotype; Pigmentation physiologic function; Pigments; Population; Process; Regulatory Pathway; Relative (related person); Research; Resources; Role; Signal Transduction; Skin; Source; Staging; Structure; Testing; Thyroid Hormones; Time; Tissues; Training; Transgenic Organisms; Vertebrates; Zebrafish; body system; cell type; comparative; developmental genetics; fetal; forward genetics; gene cloning; innovation; insight; mutant; novel; programs; public health relevance; reproductive; trait; transcriptomics; zebrafish development

DESCRIPTION (provided by applicant): We still know very little about the mechanisms that regulate and synchronize morphogenetic events during later stages of vertebrate development. Nonetheless, understanding the factors controlling these later developmental periods is essential to understanding how adult traits form, and will lend insight into morphological defects and disorders that arise during human post-embryonic fetal and neonatal periods. This research utilizes the zebrafish, which undergoes extensive post-embryonic development involving modifications and maturation in many different organ systems; many of these changes are similar or identical to processes that occur following embryogenesis in humans. This proposal employs several strategies towards understanding the mechanisms underlying the zebrafish transformation from larva to juvenile. The first aim adopts a targeted approach, testing the specific roles of thyroid hormone in post-embryonic developmental transitions. Multiple lines of evidence indicate that thyroid hormone is involved in several developmental processes in zebrafish, but the ability of this hormone to effect specific morphogenetic processes and cellular behaviors remains unclear. This aim will test roles of thyroid hormone in promoting both global somatic developmental progression and the behaviors of a specific, well-characterized cell lineage that produces adult pigmentation during the larval-to-juvenile transition. The second aim takes a forward genetic strategy to identify novel genes required for post-embryonic stage transitions. This approach has already identified two mutants that exhibit complete somatic arrest during larval development, ceasing ontogenetic progression at stages normally reached by 2- and 3-week old wild-type larvae. These phenotypes suggest an impairment of genes absolutely required for post-embryonic progression. Mapping and cloning the mutations and characterizing the pathways to which they belong will reveal mechanisms essential for post-embryonic developmental processes; continuation of this screen will identify further larval arrest phenotypes. The final aim utilizes a species related to zebrafish that exhibits a natural failure t execute the terminal stages of somatic post-embryonic development. Focusing primarily on the structure and expression within the skin, changes in genetic and developmental architecture will be elucidated in this context of post-embryonic developmental truncation. These analyses will reveal the both extent of decoupling between traits and regulatory pathways, and whether dormant genetic pathways retain responsiveness to a key endocrine mediator of post-embryonic development. Overall, these efforts will characterize the morphogenetic roles of a known endocrine regulator, will identify novel factors that regulate normal post-embryonic progression, and will establish a novel model for dissecting the ways in which developmental genetic pathways and endocrine mechanisms can evolve. Moreover, this project will complete the developmental biology and genetics training of a scholar with a background in population ecology, and will establish the foundation for her independent research laboratory.

描述（由申请人提供）：我们仍然对调节和同步脊椎动物发育阶段的形态发生事件的机制知之甚少。但是，了解控制这些后期发展时期的因素对于理解成年特征的形成至关重要，并将深入了解人类后胚胎后胎儿和新生儿时期中出现的形态缺陷和疾病。这项研究利用了斑马鱼，斑马鱼经历了许多不同器官系统中涉及修改和成熟的广泛的胚胎后发展。这些变化中的许多变化与人类胚胎发生后发生的过程相似或相同。该提案采用了几种策略来理解斑马鱼从幼虫到少年转变的机制。第一个目标采用了靶向方法，测试了甲状腺激素在胚胎后发育过渡中的特定作用。多种证据表明，甲状腺激素参与斑马鱼中的几种发育过程，但是这种激素能够影响特定的形态发生过程和细胞行为的能力尚不清楚。该目标将测试甲状腺激素在促进全球体细胞发育进展和特定，表征良好的细胞谱系的行为方面的作用，该谱系在幼虫到炎症过渡过程中产生成人色素沉着。第二个目标需要一种前瞻性的遗传策略来识别后阶段过渡所需的新基因。这种方法已经确定了两个突变体在幼虫发育过程中表现出完全的体细胞停滞，在通常在2周和3周旧的野生型幼虫的阶段中停止了个体发育进展。这些表型表明，胚胎后进展绝对需要的基因受损。映射和克隆突变并表征其所属的途径将揭示对后胚后发育过程必不可少的机制；该屏幕的继续将确定进一步的幼虫停滞表型。最终目的利用与斑马鱼有关的物种，表现出自然失败的T执行了体细胞后胚胎后发育的终端阶段。主要关注皮肤内的结构和表达，将在这种embryonic后发育截断的背景下阐明遗传和发育结构的变化。这些分析将揭示性状和监管途径之间的分离率的两种程度，以及休眠的遗传途径是否保留了对胚后发育的关键内分泌介质的反应性。总体而言，这些努力将表征已知的内分泌调节剂的形态发生作用，将确定调节正常胚胎后进展的新因素，并将建立一个新型模型，以剖析发育遗传途径和内分泌机制可以发展的方式。此外，该项目将完成具有人群生态背景的学者的发展生物学和遗传学培训，并将为她的独立研究实验室奠定基础。