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Polarity complexes in cellular differentiation

细胞分化中的极性复合物

基本信息

批准号：
RGPIN-2022-03370
负责人：
Fawcett, James
金额：
$ 3.5万
依托单位：
Dalhousie University
依托单位国家：
加拿大
项目类别：
Discovery Grants Program - Individual
财政年份：
2022
资助国家：
加拿大
起止时间：
2022-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=762085
关键词：
Polarity complexes cellular differentiation

项目摘要

A fundamental aim of my laboratory is to understand the underlying mechanisms of cellular polarity and in particular neuronal polarity. Work using polarized epithelial cells has established that three conserved core protein-protein complexes exist and are important for establishing cellular polarity in part by regulating the activity of the Hippo signaling pathway. Despite an emerging literature revealing that Hippo signaling controls cell growth and modulates cellular mechanotrasduction in non-neuronal cells, little is known about the role for Hippo signaling components in post mitotic neurons. Our NSERC funded program has focused on identifying novel polarity complexes in CNS tissues and how these function to control neuronal polarity. Our recent work has revealed a novel function for the Hippo kinase, large tumour suppressor kinase 1 (LATS1) in the stabilization of developing synapses. In non-neuronal cells, LATS1 and a related protein LATS2 function similarly in driving Hippo signaling. However, significant differences in these two proteins suggest they likely contribute to different intracellular signaling pathways. Our preliminary data reveals that in the developing nervous system, LATS1 and LATS2 have opposite expression profiles implicating LATS2 in the mature CNS. Our preliminary data also reveals that LATS2 is enriched in dendritic spines and affects both actin turnover and synapse morphology. Building on these intriguing findings, we aim to identify mechanisms by which the conserved Hippo kinase LATS2 contributes to the regulation of synaptic structural plasticity to affect neuronal function. In particular, we will: 1) Define a role for LATS2 in neuronal polarity and synaptic morphology. We will characterize how LATS2 is recruited to excitatory synapses and determine if the effects on spine morphology are kinase dependant. We will also assess the importance of LATS2 for normal cognition. 2) Characterize how LATS2 kinase activity regulates actin dynamics to regulate dendritic spine morphology. We will determine whether LATS2 directly affects actin dynamics or does so by regulating the activity of the small actin regulatory RhoGTPases, Rac, Rho or Cdc42. 3) Identify molecular pathways that function upstream of LATS2 to regulate synaptic morphology. We will test whether other known LATS2 associating proteins, KIBRA and Merlin, affect activity dependent regulation of LATS2 contributing to synapse stability. Together this work is novel, as there have been no descriptions for the contributions of the conserved LATS kinases in post mitotic neurons. Further this work will provide mechanistic insight into the role Hippo signaling components play in regulating neuronal polarity including how these signaling components contribute to the regulation of synaptic morphology and function.

我的实验室的一个基本目标是了解细胞极性，特别是神经元极性的潜在机制。使用极化上皮细胞的工作已经确定存在三种保守的核心蛋白质-蛋白质复合物，并且对于部分通过调节Hippo信号传导途径的活性来建立细胞极性是重要的。尽管新兴的文献揭示了Hippo信号控制细胞生长并调节非神经元细胞中的细胞机械转导，但对Hippo信号组分在有丝分裂后神经元中的作用知之甚少。我们的NSERC资助项目专注于识别CNS组织中的新型极性复合物以及这些复合物如何控制神经元极性。我们最近的工作揭示了一种新的功能，河马激酶，大肿瘤抑制激酶1（LATS 1）在稳定发展中的突触。在非神经元细胞中，LATS 1和相关蛋白LATS 2在驱动Hippo信号传导方面的功能相似。然而，这两种蛋白质的显著差异表明它们可能有助于不同的细胞内信号通路。我们的初步数据显示，在发育中的神经系统，LATS 1和LATS 2有相反的表达谱，暗示LATS 2在成熟的中枢神经系统。我们的初步数据还表明，LATS 2是丰富的树突棘，影响肌动蛋白营业额和突触形态。基于这些有趣的发现，我们的目标是确定保守的海马激酶LATS 2有助于调节突触结构可塑性以影响神经元功能的机制。具体而言，我们将：1）定义LATS 2在神经元极性和突触形态中的作用。我们将描述LATS 2是如何被招募到兴奋性突触的，并确定对棘形态的影响是否依赖于激酶。我们还将评估LATS 2对正常认知的重要性。2)表征LATS 2激酶活性如何调节肌动蛋白动力学以调节树突棘形态。我们将确定LATS 2是否直接影响肌动蛋白动力学或通过调节小肌动蛋白调节RhoGTPases，Rac，Rho或Cdc 42的活性来影响肌动蛋白动力学。3)确定LATS 2上游的分子通路，以调节突触形态。我们将测试是否其他已知的LATS 2相关蛋白，KIBRA和梅林，影响活动依赖的调节LATS 2有助于突触stability. Together这项工作是新颖的，因为有丝分裂后神经元中的保守的LATS激酶的贡献一直没有描述。此外，这项工作将提供机制的洞察河马信号组件在调节神经元极性的作用，包括这些信号组件如何有助于突触形态和功能的调节。