Cell type signaling specificity of the neurodevelopmental disease-associated DYRK1A kinase

神经发育疾病相关 DYRK1A 激酶的细胞类型信号传导特异性

• 批准号: 10884647
• 负责人: GEORGIA PANAGIOTAKOS
• 金额: $ 43.97万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-08 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10884647
• 关键词: Adoption; Affect; Astrocytes; Automobile Driving; Binding; Brain; Calcineurin; Calcium; Calcium Channel; Calcium Signaling; Cell Differentiation process; Cell Maintenance; Cells; Cerebral cortex; Cues; DNA Binding; Data; Development; Disease; Dose; Down Syndrome; Electroporation; Embryo; Equilibrium; Etiology; Event; Foundations; Functional disorder; Generations; Genes; Genetic; Genetic Transcription; Genetic study; Goals; Human; Human Genetics; Impairment; Intellectual functioning disability; Knowledge; L-type calcium channel alpha(1C); Link; Mental disorders; Microcephaly; Molecular; Morphology; Mouse Strains; Mus; Mutate; Mutation; NFAT Pathway; Neurodevelopmental Disorder; Neuroglia; Neuronal Differentiation; Neurons; Neurosciences; Patients; Phenocopy; Phenotype; Phosphotransferases; Play; Production; Proliferating; Publishing; Radial; Regulation; Reproducibility; Research; Role; STAT3 gene; Series; Signal Pathway; Signal Transduction; Specificity; Syndrome; Testing; Therapeutic; Thinness; Timothy syndrome; Transgenic Organisms; autism spectrum disorder; cell behavior; cell type; developmental disease; dosage; excitatory neuron; extracellular; in utero; in vivo; insight; loss of function; loss of function mutation; member; nerve stem cell; nervous system development; neural; neuron apoptosis; neuron loss; neuropsychiatric disorder; neuropsychiatry; neuroregulation; novel; nuclear factors of activated T-cells; postnatal; programs; stem; stem cells; tool; transcription factor

PROJECT SUMMARY/ABSTRACT Mutations in DYRK1A, which encodes a ubiquitously expressed kinase that antagonizes the calcium- dependent calcineurin (CaN)/NFAT signaling pathway, have been reproducibly linked to neurodevelopmental disease. DYRK1A loss of function has been associated with syndromic intellectual disability and autism spectrum disorders (ASD), and increased DYRK1A activity is thought to underlie aspects of Down Syndrome pathophysiology. These genetic clues underscore DYRK1A dosage-dependent regulation of nervous system development; however, the precise mechanisms by which DYRK1A executes its roles in the developing brain remain poorly understood. Our long-term goal is to understand how DYRK1A acts in specific cell types of the embryonic cerebral cortex to influence the commitment of neural stem and progenitor cells to specific neural fates. In the proposed studies, we focus on NFAT-dependent transcriptional mechanisms as primary effectors of DYRK1A activity in neural stem cells and their progeny. We have found that deleting Dyrk1a specifically in the developing cortex differentially impacts calcium signaling in neural stem/progenitor cells and neurons of both the mouse and human. Loss of one or both copies of Dyrk1a results in dose-dependent cortical thinning, depletion of radial glia stem cells, reduced astrocyte abundance, neuronal cell death, and shifts in excitatory neuron differentiation. Our previous studies uncovered similar changes in the generation of excitatory neuron subtypes resulting from the mutation in the Cav1.2 calcium channel that gives rise to the syndromic ASD Timothy Syndrome. Imbalances in these same excitatory neuron types have also been linked to neuropsychiatric syndromes and channelopathies, hinting that calcium-regulated molecular mechanisms may represent a core substrate underlying cellular phenotypes in ASD and other neurodevelopmental disorders. In line with this idea, we have found that the effects of Dyrk1a deletion during cortical development are phenocopied by in vivo modulation of CaN/NFAT signaling, and we have used CUT&RUN sequencing to begin to identify NFAT transcriptional targets in the developing brain. Building on these strong published and preliminary findings, the central objective of this proposal is to define cell type-specific mechanisms by which DYRK1A regulates the development of the cortex. The proposed research tests the ideas that NFAT transcriptional targets underlie deficits in stem cell maintenance and differentiation resulting from cortex-specific Dyrk1a inactivation (AIM 1), that DYRK1A and calcium signaling through CaN/NFAT play key roles in cortical astrogliogenesis (AIM 2), and that cell type-specific NFAT targets contribute to DYRK1A signaling specificity (AIM 3). These studies will build a foundation for future research expanding our knowledge of how calcium signaling regulates brain development and how ubiquitously expressed disease-relevant genes exert specific functions in different cell types. Our results will also provide therapeutic entry points for convergent intracellular mechanisms driving neurodevelopmental disorders.

项目摘要/摘要 dyRK1a中的突变，该突变编码了一个普遍表达的激酶，该激酶会拮抗钙 - 依赖性钙调神经酶（CAN）/NFAT信号通路已与神经发育相关 疾病。 DYRK1A功能丧失与综合症智力残疾和自闭症有关 频谱障碍（ASD）和增加DYRK1A活性被认为是唐氏综合症的方面 病理生理学。这些遗传线索强调了DYRK1A剂量依赖性神经系统的调节 发展;但是，DYRK1A在发育中的大脑中执行角色的确切机制 保持不当理解。我们的长期目标是了解dyrk1a在特定细胞类型中的作用 胚胎大脑皮层影响神经茎和祖细胞对特定神经的承诺 命运。在拟议的研究中，我们关注NFAT依赖性转录机制作为主要效应子 神经干细胞及其后代中的dyRK1a活性。 我们发现，在发育中的皮质中特别删除DYRK1A对钙的影响会影响钙 小鼠和人的神经干/祖细胞和神经元中的信号传导。损失一个或两个 DYRK1A的副本会导致剂量依赖性皮质稀疏，径向神经胶质干细胞的耗竭，还原 星形胶质细胞丰度，神经元细胞死亡以及兴奋性神经元分化的变化。我们以前的研究 发现了因突变而引起的兴奋性神经元亚型的产生类似变化 CAV1.2钙通道引起综合症ASD Timothy综合征。这些不平衡 兴奋性神经元类型也与神经精神综合征和通道病有关，暗示 钙调节的分子机制可能代表了核心基材的核心基材， ASD和其他神经发育障碍。与这个想法一致，我们发现dyrk1a的影响 皮质发育过程中的缺失是通过CAN/NFAT信号的体内调节来表达的，而我们 已经使用剪切和运行测序开始识别发育中大脑中的NFAT转录靶标。 在这些强大的出版和初步的发现的基础上，该提议的核心目的是定义 DYRK1A调节皮质发展的细胞类型特异性机制。提议 研究测试了NFAT转录靶标的思想是干细胞维护和 皮质特异性DYRK1A灭活产生的分化（AIM 1），DyRK1a和钙信号传导 通过CAN/NFAT在皮质星形胶质化发生中起关键作用（AIM 2），并且该细胞类型特异性NFAT靶标 有助于DYRK1A信号传导特异性（AIM 3）。这些研究将为将来的研究奠定基础 扩展我们对钙信号如何调节大脑发育以及如何普遍存在的知识 与疾病相关的基因在不同的细胞类型中发挥特定功能。我们的结果也将提供 促进神经发育障碍的收敛细胞内机制的治疗入口点。