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节，以产生 适当数量和类型的细胞;增殖或分化的失调可导致 形态发生缺陷和各种发育障碍。δ-PCDH是一个嗜同性细胞家族， 粘附分子与神经发育障碍有关，包括自闭症和癫痫。 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 揭示了缺乏单独的δ1-pCDH（pCDH 1A，pCDH 7A或pCDH 9）或δ2-pCDH（pCDH 17， pCDH 18 b或pCDH 19）在早期神经管中均显示细胞增殖增加，导致过量的神经元 后来发展。在使用体内时间推移的初步研究中，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被改变。我们进一步提供证据表明，δ- pcdh是经典Wnt信号通路的调节因子，经典Wnt信号通路和pcdh信号通路都是Wnt信号通路的调节因子。 Wnt受体Ryk是δ-pcdh突变体增殖增加所必需的。这项提案将考验 假设：1）δ-PCDH介导的细胞-细胞相互作用协调细胞增殖和神经生长， 神经上皮中的祖细胞动力学;和2）δ-pCDHS通过调节 通过Ryk的典型Wnt/β-catenin信号传导。这些实验将阐明 神经系统发育中的基本事件，并提供重要的见解， 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.