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Antagonistic interaction of polarity complex proteins in cortical development

皮质发育中极性复合蛋白的拮抗相互作用

基本信息

批准号：
10386814
负责人：
Seonhee Kim
金额：
$ 34.67万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10386814
关键词：
Actomyosin Adherens Junction Apical Architecture Binding Cell Cycle Cell Cycle Progression Cell Polarity Cell division Cells Complex Cortical Malformation Defect Development Disease Epithelial Equilibrium Generations Genes Genetic Models Goals Hippocampus (Brain)Intellectual functioning disability Intercellular Junctions Lead Link Mediating Mediator of activation protein Microcephaly Molecular Mutant Strains Mice Myosin ATPase Neonatal Neurodevelopmental Disorder Neuroepithelial Neurofibromin 2 Neurologic Symptoms Neuronal Differentiation Neurons Output PARD6A gene Pathogenesis Pathway interactions Pharmacology Problem Solving Production Regulation Regulatory Pathway Research Side Signal Transduction Structure Testing Tight Junctions Time Transcription Coactivator antagonist insight migration mutant nerve stem cell neuroepithelium neurogenesis novel periventricular heterotopia prevent progenitor protein complex restoration stem stem cells

项目摘要

The overall goal of this proposal is to elucidate the mechanisms underlying the developmental defects leading to cortical malformation by characterizing the fundamental antagonistic interactions between evolutionarily conserved polarity complex proteins. Disruption of neuroepithelial structure causes abnormalities in neuronal outputs and cortical malformation that lead to a spectrum of neurodevelopmental disorders, including periventricular heterotopia (PH), microcephaly and ventriculomegaly. Asymmetrically distributed polarity protein complexes are critical for establishing and maintaining polarized cellular architecture and for determining unequal cell fate. Two complexes (Crb/Pals1/Patj and Mupp1; Par3/Par6/aPKC), termed apical polarity complex proteins, are localized at the apical side and one basal polarity complex (Lgl/DLG/Scb) is located basolaterally. Despite its critical importance for cortical epithelial structure and progenitor cell division, it is unclear whether a well-balanced interaction between them is required for cortical structure and neurogenesis, and the cellular and molecular machinery that mediates their functional interaction is also poorly understood. To identify their essential functional interactions and the underlying molecular mechanisms, we have generated a cortical-specific Llgl1 mutant characterized by massive PH and a cortical-specific Crb2 mutant with ventriculomegaly. Remarkably, Crb1/2 loss drastically reduces heterotopia in the Llg1 mutant. It has previously been shown that Llgl1 binds to myosin and regulates its activity, and that apical polarity complex proteins aPKC and Crb2 can inhibit myosin activity. Importantly, because cellular tension and junction defects are associated with the activation of mitogenic signals such as Yap/Taz transcription coactivator, downstream effectors of the Hippo pathway, this antagonism may also be linked to abnormal proliferation that produces the enlarged heterotopic cortex found in Llgl1 CKO. These observations lead us to hypothesize that the antagonistic interaction between basal and apical polarity complexes is required to establish/localize actomyosin at the apical junction and prevent activation of an abnormal Yap/Taz- dependent mitogenic signal. To test this hypothesis, in Aim1 we will define the antagonistic relationship between apical and basal complexes in cortical progenitor proliferation and junctional integrity by analyzing mutant mice. In Aim2 we will delineate the mechanism(s) by which polarity complex proteins regulate junctional integrity by investigating the antagonistic regulation of actomyosin. Lastly, in Aim3 we will determine whether Yap-Taz regulate mitogenic signaling after polarity disruption. Our study will increase understanding of polarity complex protein interactions in cortical progenitor cell division, which will provide new insights into the pathogenesis of cortical malformation and ultimately a basis for novel treatments.

这项提案的总体目标是阐明导致发育缺陷的潜在机制，皮质畸形的特点之间的基本拮抗作用的进化保守极性复合蛋白。神经上皮结构的破坏会导致神经细胞的异常，输出和皮质畸形，导致一系列神经发育障碍，包括心室周围异位（PH）、小头畸形和心室肥大。非对称分布极性蛋白质复合物对于建立和维持极化的细胞结构以及对于决定了细胞的命运。两种复合物（Crb/Pals 1/Patj和Mupp 1; Par 3/Par 6/aPKC），称为顶端极性复合物蛋白，定位于顶端侧，并且一个基底极性复合物（Lgl/DLG/Scb）定位于顶端侧。位于基底外侧。尽管它对皮质上皮结构和祖细胞分裂至关重要，尚不清楚它们之间的良好平衡的相互作用是否是皮质结构所必需的，神经发生，以及介导其功能相互作用的细胞和分子机制也很差。明白为了确定它们的基本功能相互作用和潜在的分子机制，我们已经产生了皮质特异性Llgl 1突变体，其特征在于大量PH和皮质特异性Crb 2 心室肥大的突变体值得注意的是，Crb 1/2的丢失大大减少了Llg 1突变体的异位。它先前已经证明Llgl 1与肌球蛋白结合并调节其活性，复合蛋白aPKC和Crb 2可抑制肌球蛋白活性。重要的是，由于细胞张力和连接缺陷与促有丝分裂信号如雅普/Taz转录共激活因子的激活有关， Hippo通路的下游效应物，这种拮抗作用也可能与异常增殖有关，产生在Llgl 1 CKO中发现的扩大的异位皮质。这些观察使我们假设，需要基底和顶端极性复合物之间的拮抗相互作用，在顶端连接处建立/定位肌动球蛋白，并防止异常的雅普/Taz- 依赖的促有丝分裂信号为了检验这一假设，在Aim 1中，我们将定义拮抗关系在皮质祖细胞增殖和连接完整性的顶端和基底复合体之间，突变小鼠在Aim 2中，我们将描述极性复合物蛋白调节连接蛋白的机制。通过研究肌动球蛋白的拮抗调节，最后，在目标3中，我们将确定是否 Yap-Taz在极性破坏后调节促有丝分裂信号传导。我们的研究将增加对极性的理解复杂的蛋白质相互作用的皮质祖细胞分裂，这将提供新的见解，皮质畸形的发病机制，并最终为新的治疗方法的基础。