Protocadherin control of cell proliferation and differentiation

原钙粘蛋白控制细胞增殖和分化

基本信息

批准号：
10185073
负责人：
JAMES DAVID JONTES
金额：
$ 44.35万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-10 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10185073
关键词：
Address Adhesives Affect Asthma Brain Brain Diseases Cell Adhesion Molecules Cell Communication Cell Differentiation process Cell Line Cell Proliferation Cell division Cell physiology Cell-Cell Adhesion Cells Complex Data Defect Development Disease Epilepsy Event Family Female Gene Family Gene Mutation Genetic Goals Health Human Image Incidence Individual Lateral Lead Link Malignant Neoplasms Mechanics Mediating Molecular Mosaicism Mutation Nervous system structure Neural tube Neurodevelopmental Disorder Neuroepithelial Neuroepithelial Cells Neurons Organism Primary Neoplasm Process Production Protein Family Proteins Role Schizophrenia Signal Transduction Testing Therapeutic Time Tumor Suppressor Genes Tumor Suppressor Proteins WNT Signaling Pathway Zebrafish autism spectrum disorder base beta catenin cancer risk cell behavior cell motility cell type design developmental disease experimental study family influence gene function human disease in vivo insight mature animal member mutant nerve stem cell nervous system development neural circuit neurodevelopment neuroepithelium neurogenesis new therapeutic target protocadherin 19 receptor spatiotemporal stem cell proliferation stem cells superior colliculus Corpora quadrigemina

项目摘要

ABSTRACT During development, the division of progenitor cells is tightly regulated in time and place to produce the appropriate number and types of cells; misregulation of proliferation or differentiation can lead to morphogenetic defects and a variety of developmental disorders. The δ-pcdhs are a family of homophilic cell adhesion molecules that have been linked to neurodevelopmental disorders, including autism and epilepsy. They have additionally been identified as tumor suppressor genes in an array of cancers. Our preliminary data reveal that mutant zebrafish lacking individual δ1-pcdhs (pcdh1a, pcdh7a or pcdh9) or δ2-pcdhs (pcdh17, pcdh18b or pcdh19) all display increased cell proliferation in the early neural tube, resulting in excess neurons later in development. In a preliminary study using in vivo timelapse, we show by direct observation that the spatiotemporal dynamics of cell divisions is altered in the mutants. We further provide evidence that the δ- pcdhs are regulators of the canonical Wnt signaling pathway and that both canonical Wnt signaling and the Wnt receptor Ryk are required for the increased proliferation in δ-pcdh mutants. This proposal will test the hypotheses that: 1) cell-cell interactions, mediated by δ-pcdhs, coordinate cell proliferation and neural progenitor cell dynamics in the neuroepithelium; and 2) δ-pcdhs influence cell proliferation by regulating canonical Wnt/β-catenin signaling through Ryk. These experiments will elucidate the mechanics of fundamental events in nervous system development and provide important insights both into the underlying causes of neurodevelopmental disease and to the role of δ-pcdhs in cancer.

抽象的在开发过程中，祖细胞的分裂在时间和地点受到严格调节，以产生适当的细胞数量和类型；扩散或差异化的不正体可能导致形态发生缺陷和多种发育障碍。 δ-PCDH是一个同粒细胞的家族与神经发育障碍有关的粘附分子，包括自闭症和癫痫。它们还被确定为癌症阵列中的肿瘤抑制基因。我们的初步数据揭示缺乏单个Δ1-PCDHS（PCDH1A，PCDH7A或PCDH9）或Δ2-PCDHS（PCDH17，PCDH17）的突变斑马鱼 PCDH18B或PCDH19）所有显示早期神经元中细胞增殖的增加后来开发。在使用体内时间解脱的初步研究中，我们通过直接观察表明细胞分裂的时空动力学在突变体中发生了改变。我们进一步提供了δ-的证据 PCDH是规范Wnt信号通路的调节剂，并且既有规范的Wnt信号传导又是 Wnt接收器RYK是Δ-PCDH突变体增殖增加所必需的。该建议将测试假设：1）通过Δ-PCDH介导的细胞 - 细胞相互作用，坐标细胞增殖和中性神经皮细胞中的祖细胞动力学； 2）δ-PCDHS通过调节影响细胞增殖经典的Wnt/β-catenin通过RYK信号传导。这些实验将阐明神经系统发展中的基本事件，并为基础的重要见解提供重要的见解神经发育疾病的原因和Δ-PCDH在癌症中的作用。