REGULATION OF DENDRITE MORPHOGENESIS BY A CONTROSOMAL CAMKIIB SIGNALING PATHWAY

对照体 CAMKIIB 信号通路对树突形态发生的调节

• 批准号: 9269270
• 负责人: AZAD BONNI
• 金额: $ 37.53万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9269270
• 关键词: Address; Biochemical; Brain; Brain Diseases; C-terminal; Centrosome; Cerebellar cortex structure; Cognition Disorders; Complex; Cytoplasmic Granules; Data; Dendrites; Development; Dissociation; Fluorescence Recovery After Photobleaching; Goals; Growth; HDAC6 gene; Immunoglobulin Variable Region; Intellectual functioning disability; Label; Light; Link; Mass Spectrum Analysis; Microtubules; Molecular; Morphogenesis; Morphology; N-terminal; Nature; Neurons; Pathogenesis; Pattern; Peptides; Phosphorylation; Phosphotransferases; Protein Isoforms; Protein Kinase; Proteins; Rattus; Regulation; Research; Rodent; Role; Signal Pathway; Signal Transduction; Specific qualifier value; Structure; TRP channel; TSC1 gene; Testing; Ubiquitin; autism spectrum disorder; base; calmodulin-dependent protein kinase II; chemical genetics; experimental study; in vivo; innovation; insight; knock-down; multicatalytic endopeptidase complex; nervous system disorder; neural circuit; novel; public health relevance; ubiquitin ligase

DESCRIPTION (provided by applicant): The long-term goals of the proposed research are to elucidate the signaling mechanisms regulating neuronal morphogenesis and connectivity in the mammalian brain. The major protein kinase CaMKII predominantly consists of the Alpha and Beta isoforms in the brain. Although CaMKIIBeta functions have been elucidated, the isoform- specific catalytic functions of CaMKIIBeta have remained largely unexplored. Using rigorously controlled knockdown analyses in primary rat neurons and in the rodent cerebellar cortex in vivo, we recently discovered the first unique catalytic function of CaMKIIBeta in the mammalian brain. Remarkably, CaMKIIBeta operates at the centrosome in a CaMKIIAlpha-independent manner to drive dendrite retraction and pruning. In other studies, we found that the TRP channel TRPC5 forms a specific complex with CaMKIIBeta, but not CaMKIIAlpha, and thereby triggers the activation of centrosomal CaMKIIBeta signaling leading to dendrite retraction and pruning in granule neurons and in the cerebellar cortex in vivo. Our findings define a novel TRPC5-regulated centrosomal CaMKIIBeta signaling pathway that controls dendrite patterning in the mammalian brain. Our findings also raise fundamental questions on the molecular basis of TRPC5-regulation of CaMKIIBeta signaling at the centrosome and the mechanisms by which centrosomal CaMKIIBeta regulates dendrite morphogenesis. To address these questions, in structure-function analyses we will test the hypothesis that distinct peptide motifs within TRPC5 and CaMKIIBeta specify the TRPC5/CaMKIIBeta interaction and thereby regulate dendrite patterning in the rodent cerebellar cortex in vivo. Using candidate and innovative unbiased biochemical approaches, we will identify novel substrates of centrosomal CaMKIIBeta and determine their role in the CaMKIIBeta-regulation of dendrite morphogenesis in granule neurons and in the rodent cerebellar cortex in vivo. Finally, in recent exciting studies, we have discovered that proteasomes operate at the centrosome to promote dendrite growth. Based on preliminary data, we will test the hypothesis that centrosomal CaMKIIBeta signaling regulates proteasome activity at the centrosome and thereby controls dendrite morphogenesis. The proposed research represents an important set of experiments that will advance our understanding of the mechanisms that control dendrite patterning and connectivity in the mammalian brain. Since disruption of dendrite connectivity contributes to the pathogenesis of diverse neurological diseases including intellectual disability and autism spectrum disorders, our studies will also advance our understanding of these devastating neurological diseases.

描述（由申请人提供）：拟议研究的长期目标是阐明哺乳动物大脑中调节神经元形态发生和连接的信号传导机制。主要的蛋白激酶CaMKII主要由脑中的α和β同种型组成。虽然CaMKIIBeta的功能已经阐明，但CaMKIIBeta的同种型特异性催化功能仍在很大程度上未被探索.在原代大鼠神经元和啮齿动物小脑皮质中使用严格控制的敲除分析，我们最近发现了哺乳动物大脑中CaMKIIBeta的第一个独特的催化功能。值得注意的是，CaMKIIIBeta在中心体中以CaMKIIAlpha独立的方式驱动树突收缩和修剪。在其他研究中，我们发现TRP通道TRPC 5与CaMKIIBeta形成特异性复合物，但不与CaMKII Alpha形成特异性复合物，从而触发中心体CaMKIIBeta信号传导的激活，导致颗粒神经元和小脑皮质中的树突收缩和修剪。我们的研究结果定义了一种新的TRPC 5调节的中心体CaMKIIBeta信号通路，控制哺乳动物大脑中的树突图案。我们的研究结果还提出了根本性的问题TRPC 5调节CaMKIIBeta信号在中心体和中心体CaMKIIBeta调节树突形态发生的机制的分子基础。为了解决这些问题，在结构-功能分析，我们将测试的假设，不同的肽基序内TRPC 5和CaMKIIBeta指定的TRPC 5/CaMKIIBeta相互作用，从而调节树突图案在啮齿动物小脑皮质在体内。使用候选人和创新的公正的生化方法，我们将确定新的基板的中心体CaMKIIBeta和确定其作用的CaMKIIBeta调节树突形态发生在颗粒神经元和啮齿动物小脑皮质在体内。最后，在最近令人兴奋的研究中，我们发现蛋白酶体在中心体中起作用，促进树突生长。基于初步的数据，我们将测试的假设，中心体CaMKIIBeta信号调节蛋白酶体活性的中心体，从而控制树突形态发生。拟议的研究代表了一组重要的实验，将促进我们对哺乳动物大脑中控制树突图案和连接的机制的理解。由于树突连接的破坏有助于多种神经系统疾病的发病机制，包括智力残疾和自闭症谱系障碍，我们的研究也将促进我们对这些毁灭性神经系统疾病的理解。