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Nf2-dependent regulation of neuronal scaling in the developing cerebellum

发育中小脑神经元缩放的 Nf2 依赖性调节

基本信息

批准号：
10646360
负责人：
Viktor Chizhikov
金额：
$ 42.64万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-15 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10646360
关键词：
Affect Ataxia Brain Brain Diseases Candidate Disease Gene Cell Fate Control Cell Lineage Cell secretion Cells Central Nervous System Cerebellar Cortex Cerebellar Diseases Cerebellum Cerebrospinal Fluid Cytoplasmic Granules Cytoskeleton Data Data Set Dependence Development Electroporation Embryo Equilibrium Fetal Growth Retardation Foundations Generations Genes Genetic Human Interneurons Intrinsic factor Lip structure Malignant Neoplasms Maps Mediating Mitogens Molecular Motor Mus Neurofibromatosis 2 Neurofibromin 2 Neuroglia Neurons Output Pathogenesis Pathway interactions Phenotype Phosphorylation Site Population Pregnancy Complications Premature Birth Process Production Proliferating Proteins Purkinje Cells RNA analysis Regulation Role SHH gene Spinocerebellar Ataxias System Testing Time Ventricular autism spectrum disorder beta catenin cell type cognitive function conditional knockout design developmental disease gain of function granule cell in utero in vivo inhibitor insight loss of function migration mutant nerve stem cell nervous system disorder neural neural circuit non-genetic novel overexpression prevent progenitor prospective regenerative therapy response restraint smoothened signaling pathway stem cells transcriptome sequencing ubiquitin ligase white matter

项目摘要

Summary The production of different types of neurons in the appropriate proportions, called neuronal scaling, is critical for the formation of functional neural circuits and proper excitatory/inhibitory balance. Disruption of neuronal scaling contributes to the pathogenesis of developmental brain disorders, including spinocerebellar ataxia and autism. Although significant progress has been made toward understanding the differentiation of specific neurons, little is known regarding the mechanisms that scale the number of functionally related neurons in the brain. The cerebellum contains only few neuronal cell types, the developmental origins of which are well- established. Thus, the cerebellum is an ideal system to study the mechanisms of neuronal scaling. In the cerebellum, both rhombic lip-derived excitatory granule neurons and ventricular zone-derived inhibitory interneurons are scaled relative to Purkinje cells, the only output neurons from the cerebellar cortex. Purkinje cells control the number of granule cells by secreting the Sonic hedgehog (Shh) protein, which promotes the proliferation of granule cell precursors and the expansion of progenitors in the prospective white matter (pWM) that give rise to inhibitory interneurons. Before migrating to the pWM, neural progenitors proliferate in the cerebellar ventricular zone (cVZ), which also gives rise to Purkinje cell layer progenitors (PCLPs), which during normal development produce exclusively glia. While Shh production by Purkinje cells and Shh transduction in granule cell precursors has been studied intensively, the neuronal scaling mechanisms that act intrinsically in cVZ-derived cells are poorly understood. In our preliminary studies, we found that loss of the Neurofibromatosis 2 (Nf2) gene results in a unique phenotype with disrupted scaling of both granule cells and inhibitory interneurons relative to Purkinje cells. Excitingly, our conditional knockout analysis in mice revealed that Nf2 controls neuronal scaling in the cerebellum acting intrinsically in cVZ-derived cells to regulate several distinct, poorly understood developmental steps. This proposal will characterize the molecular mechanisms that regulate neuronal scaling in the cerebellum, using Nf2 as an entry point, in three complementary Aims. In Aim 1, we will investigate how Nf2 coordinates the proliferation and migration of progenitors in the cVZ, identifying novel Nf2 downstream targets that regulate each of these processes. In Aim 2, we will define an Nf2-dependent pathway that regulates the expansion and proliferative response to Shh of pWM progenitors. In Aim 3, we will identify Nf2-dependent mechanisms that inhibit the misspecification of PCLPs into granule cells, preventing the production of excessive granule cells during normal development. Our studies will identify basic mechanisms that regulate development of the cerebellum, a major center of motor coordination and cognitive functions, will provide novel insights into human cerebellar developmental disorders, and help the development of brain regeneration therapies.

摘要以适当的比例产生不同类型的神经元，称为神经元伸缩，是至关重要的以形成功能神经回路和适当的兴奋/抑制平衡。神经元性断裂 Scaling有助于发育性大脑疾病的发病机制，包括脊髓小脑性共济失调和自闭症。尽管在理解特定词的区别方面已经取得了重大进展神经元，关于调节脑内功能相关神经元数量的机制知之甚少。大脑。小脑只含有几种神经细胞类型，其发育起源是很好的- 已经成立了。因此，小脑是研究神经元伸缩机制的理想系统。在小脑，菱形唇源性兴奋性颗粒神经元和脑室带源性抑制中间神经元相对于浦肯野细胞进行缩放，浦肯野细胞是小脑皮质唯一的输出神经元。浦肯野细胞通过分泌Sonic Hedgehog(Shh)蛋白来控制颗粒细胞的数量，Sonic Hedgehog(Shh)蛋白促进预期白质中颗粒细胞前体细胞的增殖和祖细胞的扩张这会产生抑制性中间神经元。在迁移到脉宽调制之前，神经前体细胞在小脑室带(CVZ)，这也产生浦肯野细胞层祖细胞(PCLP)，这在正常发育只产生神经胶质细胞。而浦肯野细胞产生Shh和Shh转导颗粒细胞前体已经被深入研究，神经元的伸缩机制内在地作用于人们对CVZ来源的细胞知之甚少。在我们的初步研究中，我们发现神经纤维瘤病2(NF2)基因导致一种独特的表型，颗粒细胞和与浦肯野细胞相关的抑制性中间神经元。令人兴奋的是，我们对小鼠的条件性基因敲除分析揭示了 NF2控制小脑中神经元的伸缩，在CVZ来源的细胞中内在地作用于调节几个不同的、鲜为人知的发展步骤。这项提议将描述分子机制它以NF2为切入点，在三个互补的目标中调节小脑中的神经元伸缩。在……里面目的1，我们将研究NF2如何协调CVZ中祖细胞的增殖和迁移，确定调控这些过程中每一个过程的新的NF2下游目标。在目标2中，我们将定义一个 NF2依赖的途径，调节PWM前体细胞对Shh的扩张和增殖反应。在……里面目的3，我们将确定NF2依赖的机制，抑制PCLP错误指定为颗粒细胞，防止正常发育过程中产生过多的颗粒细胞。我们的研究将确定基本的调节小脑发育的机制，小脑是运动协调和认知的主要中心功能，将为人类小脑发育障碍提供新的见解，并有助于大脑再生疗法。