CaM-kinase I regulation of synaptic development via MeCP2

CaM-激酶 I 通过 MeCP2 调节突触发育

• 批准号: 8003121
• 负责人: Mary Heng
• 金额: $ 5.05万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-21 至 2011-09-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8003121
• 关键词: Actins; Address; Autopsy; Brain; Brain-Derived Neurotrophic Factor; CREB1 gene; CaM kinase I activator; Childhood; Development; Disease; Dominant-Negative Mutation; Down Syndrome; Exhibits; Fragile X Syndrome; Genetic Transcription; MEKs; Maps; Methyl-CpG-Binding Protein 2; Pathogenesis; Pathway interactions; Phospho-Specific Antibodies; Phosphotransferases; Play; Proteins; RNA Interference; Regulation; Repressor Proteins; Rett Syndrome; Role; Signal Pathway; Signal Transduction; Synapses; Technology; Transcription Repressor/Corepressor; Transfection; Translations; Vertebral column; brain volume; calmodulin-dependent protein kinase I; developmental disease; inhibitor/antagonist; neuropsychiatry; public health relevance; synaptogenesis

DESCRIPTION (provided by applicant): Synaptic maturation is critical for brain development. Dendritic arborization and spine/synapse formation are regulated in part by localized Ca2+ dynamics. Alterations in synaptic development are a fundamental feature of abnormal brain development in several childhood developmental disorders including Rett syndrome (RTT), Fragile X syndrome, and Down syndrome. Postmortem Rett brains exhibit reduced brain volume and marked reduction of dendritic development, maturation, and branching. Recent findings demonstrate that translation of MeCP2, the transcriptional repressor protein involved in RTT, is suppressed by CREB-dependent transcription of microRNA132 (miR132). Activity-dependent activation of CREB and formation of miR132 is regulated by the CaMKK/CaMKI/MEK/ERK signaling pathway. This pathway has previously been established to play a critical role in the normal development of dendritic arborization and synapse maturation. We propose to investigate the CaMKK/CaMKI signaling pathway as a potential mechanism regulating MeCP2-dependent synaptogenesis in the following specific aims: (1) CaMKI, via regulation of CREB-dependent miR132, maintains appropriate levels of MeCP2 to allow synaptogenesis; (2) alternatively, MeCP2 regulates expression of BDNF, thereby activating CaMKI which is known to modulate actin dynamics and synapse formation via Rac and Pak. In Aims 1 and 2 we will utilize multiple, independent approaches to map these signaling pathways: phospho-specific antibodies to assess the activation state of signaling components, a variety of pharmacological inhibitors, transfection of dominant-negative and constitutively-active signaling constructs, and RNAi technologies to suppress endogenous proteins. These multiple approaches are necessary since each individually has limitations. PUBLIC HEALTH RELEVANCE: These findings may contribute to the understanding of the pathogenesis of a spectrum of neurodevelopmental and neuropsychiatric disorders that exhibit abnormal spine development. Addressing how CaM kinase signaling pathways are involved in synaptogenesis may therefore provide new avenues for the therapy of RTT and other childhood developmental disorders associated with MeCP2 and abnormal spine development.

描述（由申请人提供）：突触成熟对于大脑发育至关重要。树突状树博化和脊柱/突触的形成部分通过局部CA2+动力学调节。突触发育的改变是多种儿童发育障碍中脑发育异常发育的基本特征，包括RETT综合征（RTT），脆弱的X综合征和唐氏综合症。验尸大脑显示出脑体积减少，并且树突状发育，成熟和分支的显着降低。最近的发现表明，MeCP2的转录阻遏蛋白的翻译被MicroRNA132的CREB依赖性转录抑制（miR132）。 CAMKK/CAMKI/MEK/ERK信号通路调节CREB的活性依赖性激活和MIR132的形成。以前已经建立了该途径在树突木化和突触成熟的正常发展中发挥关键作用。我们建议将CAMKK/CAMKI信号通路作为一种潜在的机制，以调节以下特定目的调节MECP2依赖性突触发生：（1）CAMKI通过调节CREB依赖性miR132，维持适当的MECP2水平以允许突触发生； （2）或者，MECP2调节BDNF的表达，从而激活CAMKI，该CAMKI已知可以通过RAC和PAK调节肌动蛋白动力学和突触形成。在目标1和2中，我们将利用多种独立的方法来绘制以下信号通路：磷酸特异性抗体评估信号传导成分的激活状态，多种药理抑制剂，主导性生物学和组成性活性信号传导构建体的转染以及RNAI技术，以及RNAI技术，以抑制内源性蛋白质。这些多种方法是必要的，因为每个方法都有局限性。 公共卫生相关性：这些发现可能有助于理解表现出异常脊柱发育的神经发育和神经精神疾病的发病机理。因此，解决突触发生的CAM激酶信号通路如何与MECP2和异常脊柱发育有关的RTT和其他儿童发育障碍的治疗提供了新的途径。