Development of Distinct Neural Crest and Hematopoietic Subpopulations

描述（由申请人提供）：阐明胚胎细胞群体分化为多个不同的衍生子服务于特定功能的遗传调控是发育生物学的核心问题。神经嵴是一个短暂的胚胎前体细胞群，它产生了各种各样的细胞衍生物，包括周围神经系统的神经元和胶质细胞，色素细胞和颅面骨骼的成分等。同样，来源于侧板中胚层的造血祖细胞最终产生多种血细胞类型，包括红细胞、髓细胞和淋巴细胞衍生物以及脉管系统细胞。尽管神经嵴和造血谱系已被广泛研究，但对这些谱系多样化的遗传调控的阐明仍然不完整。本研究的主要目标是为神经嵴和造血前体的遗传调控以及不同神经嵴和造血亚群的规范和发展提供新的见解。我们将确定两个谱系发育的关键调节因子的功能，并阐明细胞多样化的遗传途径和网络。我们将利用斑马鱼突变体，这些突变体在造血和/或神经嵴发育方面显示出特定和严重的缺陷。我们提出了一个由相互关联的实验方法组成的研究计划，以分析已知的关键调控基因和这些突变位点对应的基因在神经嵴发育和造血的遗传调控中的作用。我们将系统地评估这些基因在神经嵴和造血祖细胞的产生、发育不同亚谱系的规范和发展以及源自这些祖细胞的分化细胞类型的产生中的作用。这些分析将确定这些基因在调节细胞存活和/或为这些谱系的细胞多样化提供所需的指导线索中的作用。此外，我们的研究结果将进一步确定神经嵴发育和造血的关键遗传调控因子的独特和重叠功能，并确定来自外胚层（神经嵴）和中胚层（造血）的细胞发育的关键基因。我们期望这些研究结果将为神经嵴发育和造血的具体调控机制以及胚胎细胞多样化提供重要的新见解。此外，由于神经嵴发育和造血过程中的错误导致人类许多临床相关疾病，我们的研究结果可能为人类疾病的诊断和治疗策略的发展提供信息。

DESCRIPTION (provided by applicant): Elucidation of the genetic regulation of the diversification of embryonic cell populations into multiple distinct derivatives sub-serving specialized functions is a central issue in developmental biology. The neural crest is a transient embryonic population of precursor cells that gives rise to a diverse array of cellular derivatives including neurons and glia of the peripheral nervous system, pigment cells and elements of the craniofacial skeleton, among others. Similarly, hematopoietic progenitors derived from lateral plate mesoderm ultimately generate multiple blood cell types including erythroid, myeloid and lymphoid derivatives as well as cells of the vasculature. Although both neural crest and hematopoietic lineages have been studied extensively, elucidation of the genetic regulation of the diversification of these lineages remains incomplete. The major goals of this proposal are to provide new insights into the genetic regulation of the generation of neural crest and hematopoietic precursors and the specification and development of distinct neural crest and hematopoietic subpopulations. We will determine the functions of critical regulators of the development of both lineages and elucidate the genetic pathways and networks that underlie cell diversification. We will utilize zebrafish mutants that display specific and severe defects in hematopoiesis and/or neural crest development. We propose a research plan comprised of inter-related experimental approaches to analyze the contributions of known critical regulatory genes and genes corresponding to these mutant loci in the genetic regulation of neural crest development and hematopoiesis. We will systematically assess the roles of these genes in the generation of neural crest and hematpoietic progenitors, the specification and development of developmentally distinct sublineages and the generation of differentiated cells types derived from these progenitors. These analyses will determine the roles of these genes in regulating cell survival and/or providing instructional cues required for the cellular diversification of these lineages. Additionally, our results will further define unique and overlapping functions of key genetic regulators of neural crest development and hematopoiesis and also identify genes critical for the development of cells derived from both ectoderm (neural crest) and mesoderm (hematopoiesis). We expect that the results of these studies will provide significant new insights into the mechanisms that regulate neural crest development and hematopoiesis specifically, and embryonic cell diversification generally. In addition, because miscues during neural crest development and hematopoiesis result in numerous clinically relevant conditions in humans, our results are likely to provide information leading to the development of strategies for the diagnosis and treatment of human diseases.