THE ROLE OF prdm1 IN BRANCHIAL ARCH DEVELOPMENT

描述（申请人提供）：为了产生颅面骨骼，神经嵴祖细胞需要采用一种特定的命运。确定神经嵴细胞及其衍生物的细胞命运决定调控的分子机制是我实验室的长期目标。神经嵴细胞起源于神经板的外侧部分，并广泛迁移形成颅面骨架以及其他衍生物。本应用的具体目的是确定斑马鱼和小鼠鳃弓中对prdm1的遗传需求，确定prdm1在鳃弓中的遗传相互作用，并确定prdm1是否积极调节斑马鱼和小鼠鳃弓中神经嵴衍生间质的细胞增殖和/或分化。我们的假设是，prdm1对神经嵴细胞分化的形成至关重要。提出了一系列实验来验证这一假设。我们建议验证prdm1在神经嵴间质分化为角状鳃裂骨骼所需的假设。此外，我们将确定prdm1周围的遗传等级，以验证prdm1在关键颅面调节因子的下游和与hand2处于同一水平的假设。最后，我们将验证prdm1通过促进前体细胞增殖来促进细胞分化的假设，而不影响细胞命运，并且在斑马鱼和小鼠的神经嵴衍生间质中都是必需的。为了实现这些目标，我们将利用斑马鱼和小鼠系统，因为它们完善的实验和遗传方法使这一过程的详细分析变得可行。作为这些研究的结果，我们有望确定prdm1转录因子在神经嵴细胞的分化中起关键作用。这对于确定神经嵴发育的重要遗传途径非常重要，而神经嵴发育又将是预防人类先天性缺陷（如唇裂和腭裂）的重要一步。

DESCRIPTION (provided by applicant): In order to generate the craniofacial skeleton, neural crest progenitors need to adopt one specific fate verses another. It is the long-term goal of my laboratory to determine the molecular mechanisms that regulate cell fate determination of neural crest cell and their derivatives. Neural crest cells arise from the lateral portion of the neural plate and migrate extensively to form the craniofacial skeleton as well as other derivatives. The specific objective of this application is to determine the genetic requirement for prdm1 in the branchial arches of zebrafish and mouse, to determine the genetic interactions of prdm1 in the branchial arch, and to determine whether prdm1 actively regulates cell proliferation and/or differentiation in neural crest derived mesenchyme in the branchial arches of zebrafish and mouse. Our hypothesis is that prdm1 is crucial for formation of neural crest cell differentiation. A series of experiments to test this hypothesis is proposed. We propose to test the hypothesis that prdm1 required within the branchial arch for differentiation of the neural crest derived mesenchyme into ceratobranchial skeleton. In addition, we will determine the genetic hierarchy around prdm1 to test the hypothesis that prdm1 acts downstream of key craniofacial regulators and at the same level as hand2. Lastly, we will test the hypothesis that prdm1 acts to promote cell differentiation by promoting the proliferation of precursor cells, without affecting cell fate and is required within the neural crest derived mesenchyme in both zebrafish and mouse. Towards these goals, we will take advantage of the zebrafish and the mouse systems, because of their well-established experimental and genetic methods make a detailed analysis of this process feasible. As an outcome of these studies, it is expected to determine that the prdm1 transcription factor plays critical role in the differentiation of neural crest cells. This will be important in determining the genetic pathways that are important for neural crest development, which in turn will be an important step in preventative measures in human congenital defects, such as cleft lip and palate.