Protocadherin control of cell proliferation and differentiation

摘要 在发育过程中，祖细胞的分裂在时间和地点上受到严格调控，以产生 适当数量和类型的细胞；增殖或分化调节不当可导致 形态发生缺陷和各种发育障碍。δ-pcdh是一类嗜同型细胞 黏附分子与神经发育障碍有关，包括自闭症和癫痫。 此外，它们还被鉴定为一系列癌症中的肿瘤抑制基因。我们的初步数据 揭示了缺少单个δ1-PCdhs(pcdh1a、pcdh7a或pcdh9)或δ2-pcdhs(pcdh17， Pcdh18b或pcdh19)都表现出早期神经管中细胞增殖增加，导致神经元过剩。 在以后的开发中。在一项使用体内时间流逝的初步研究中，我们通过直接观察表明 在突变体中，细胞分裂的时空动态发生了改变。我们进一步提供证据证明δ- PCdhs是典型的Wnt信号通路的调节者，并且规范的Wnt信号和 在δ-pcdh突变体中，WnT受体Ryk是促进增殖所必需的。这项提案将考验 假设：1)细胞间的相互作用，由δ-pcdhs介导，协调细胞增殖和神经 神经上皮祖细胞动力学；2)δ-pcdhs通过调控细胞增殖影响细胞增殖 经典的Wnt/β-连环蛋白通过Ryk信号转导。这些实验将阐明 神经系统发育中的基本事件，并提供对潜在的 神经发育疾病的原因以及δ-PCdhs在癌症中的作用。

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.