Development of Distinct Neural Crest and Hematopoietic Subpopulations

描述(由申请人提供)：阐明胚胎细胞群体多样化为多个不同的、具有特殊功能的衍生体的遗传调控是发育生物学的中心问题。神经脊是一个由前体细胞组成的瞬时胚胎群体，它产生了一系列不同的细胞衍生品，包括周围神经系统的神经元和神经胶质细胞、色素细胞和头面部骨骼的元素等。同样，来自侧板中胚层的造血祖细胞最终会产生多种血细胞类型，包括红系、髓系和淋巴系以及血管系统的细胞。尽管神经脊系和造血系都得到了广泛的研究，但对这些系系多样化的遗传调控仍未阐明。这一建议的主要目的是对神经脊和造血前体的产生的遗传调控以及不同的神经脊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，并阐明支撑细胞多样化的遗传途径和网络。我们将利用在造血和/或神经脊发育方面表现出特定和严重缺陷的斑马鱼突变体。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与这些突变基因相对应的基因在神经脊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脊和造血祖细胞的产生、发育不同亚系的指定和发育以及从这些祖细胞衍生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生存方面的作用和/或提供这些谱系的细胞多样化所需的指导线索。此外，我们的结果将进一步确定神经脊发育和造血的关键遗传调节因子的独特和重叠功能，并识别对来自外胚层(神经脊)和中胚层细胞(造血)的细胞发育至关重要的基因。我们期望，这些研究的结果将提供重要的新见解，特别是调节神经脊发育和造血的机制，以及总体上胚胎细胞的多样化。此外，由于神经脊发育和造血过程中的失误会导致人类出现许多临床相关的疾病，我们的结果可能会为制定人类疾病的诊断和治疗策略提供信息。

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.