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

基本信息

项目摘要

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基因突变,它编码一种无处不在的表达的激酶,对抗钙离子- 依赖的钙调神经磷酸酶(CaN)/NFAT信号通路与神经发育密切相关 疾病。DYRK1a功能丧失与综合征性智力残疾和自闭症有关 谱系障碍(ASD)和DYRK1A活性增加被认为是唐氏综合症的基础 病理生理学。这些遗传线索强调了DYRK1a对神经系统的剂量依赖性调节 然而,DYRK1A在发育中的大脑中发挥其作用的确切机制 人们对此仍然知之甚少。我们的长期目标是了解DYRK1A如何在特定类型的细胞中发挥作用 胚胎大脑皮层影响神经干祖细胞对特定神经的定位 命运。在所提出的研究中,我们将重点放在nfat依赖的转录机制作为主要效应因子。 神经干细胞及其后代中DYRK1A活性的研究。 我们已经发现,在发育中的皮质中特异性地删除Dyrk1a会对钙产生不同的影响 小鼠和人的神经干细胞/祖细胞和神经元中的信号。失去一个或两个 复制Dyrk1a导致剂量依赖的皮质变薄,放射状胶质干细胞耗竭,减少 星形胶质细胞的丰富,神经细胞死亡,以及兴奋性神经元分化的转变。我们之前的研究 在兴奋性神经元亚型的产生中发现了类似的变化,这是由基因突变引起的 Cav1.2钙通道导致综合征ASD Timothy综合征。在这些相同的地方不平衡 兴奋性神经元类型也与神经精神综合征和通道病有关,这暗示 钙调节的分子机制可能代表了支持细胞表型的核心底物 ASD和其他神经发育障碍。根据这一观点,我们发现Dyrk1a的影响 大脑皮质发育过程中的缺失是通过体内调节CaN/NFAT信号来表现出来的,我们 已经使用切割和运行测序开始识别NFAT在发育中的大脑中的转录靶点。 在这些强有力的已发表和初步调查结果的基础上,这项提案的中心目标是界定 DYRK1a调节皮质发育的细胞类型特异性机制。建议数 研究验证了NFAT转录靶点是干细胞维持和修复缺陷的基础的想法 皮层特异性Dyrk1a失活(AIM 1)引起的分化,DYRK1a和钙信号转导 通过CaN/NFAT在皮质星形胶质细胞发生(AIM-2)中起关键作用,而该细胞类型特异性的NFAT靶点 有助于DYRK1A信号的特异性(AIM 3)。这些研究将为今后的研究奠定基础 扩大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 表达的疾病相关基因在不同的细胞类型中发挥特定的功能。我们的结果还将提供 推动神经发育障碍的细胞内趋同机制的治疗切入点。

项目成果

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GEORGIA PANAGIOTAKOS其他文献

GEORGIA PANAGIOTAKOS的其他文献

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{{ truncateString('GEORGIA PANAGIOTAKOS', 18)}}的其他基金

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:
    10522818
  • 财政年份:
    2022
  • 资助金额:
    $ 43.97万
  • 项目类别:
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:
    10424698
  • 财政年份:
    2021
  • 资助金额:
    $ 43.97万
  • 项目类别:
Calcium-Dependent Regulation of Neural Fate in Development and Disease
发育和疾病中神经命运的钙依赖性调节
  • 批准号:
    10513828
  • 财政年份:
    2020
  • 资助金额:
    $ 43.97万
  • 项目类别:
Calcium-Dependent Regulation of Neural Fate in Development and Disease
发育和疾病中神经命运的钙依赖性调节
  • 批准号:
    10320788
  • 财政年份:
    2020
  • 资助金额:
    $ 43.97万
  • 项目类别:
L-type Calcium Channel Regulation of Neuronal Differentiation
L型钙通道对神经元分化的调节
  • 批准号:
    8073115
  • 财政年份:
    2010
  • 资助金额:
    $ 43.97万
  • 项目类别:
L-type Calcium Channel Regulation of Neuronal Differentiation
L型钙通道对神经元分化的调节
  • 批准号:
    8325694
  • 财政年份:
    2010
  • 资助金额:
    $ 43.97万
  • 项目类别:
L-type Calcium Channel Regulation of Neuronal Differentiation
L型钙通道对神经元分化的调节
  • 批准号:
    7909748
  • 财政年份:
    2010
  • 资助金额:
    $ 43.97万
  • 项目类别:

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