Transcriptional regulation, neuronal development, and function of the mushroom body in a Drosophila model of intellectual disability

智力障碍果蝇模型中的转录调节、神经元发育和蘑菇体的功能

基本信息

项目摘要

ABSTRACT Intellectual disability (ID) disorders affect 2% of the population and are characterized by an IQ score lower than 70 with deficits in adaptive functioning. Mutations in over 400 genes contribute to the pathogenesis of ID disorders, with patients presenting with learning and memory impairments and often syndromic features such as epilepsy, anxiety, short stature, and aggressive tendencies. Our research focusses on the KDM5 family of transcriptional regulators, mutations in which account for 1-3% of inherited ID ranging from mild to severe. The molecular mechanisms by which KDM5 proteins impact neuronal function remain largely unknown, leaving patients without effective treatment strategies. Thus, the overarching goal of this project will be to understand how mutations in KDM5 contribute to neuronal and transcriptional outputs that influence cognition. Here, we will utilize the genetically tractable Drosophila, which encodes a single ortholog of kdm5, to investigate neuronal morphology, transcriptional outputs, and behavioral phenotypes of flies bearing patient-derived KDM5 missense mutations. We have generated a set of ten fly strains, each of which harbors a conserved mutation in Drosophila kdm5 that is analogous to an ID-associated allele. Preliminary data have demonstrated that RNAi-mediated knockdown of kdm5 results in profound guidance and growth defects of the mushroom body (MB), a paired neuropil-rich structure required for the acquisition, consolidation, and retrieval of long- and short-term memory. Significantly, similar morphological MB defects are observed in flies bearing a mutation analogous to an ID- causing missense mutation in an A/T rich interacting domain (ARID) previously implicated in KDM5 DNA binding. Based on these and other data, our central hypothesis is that KDM5 is essential for MB development, and that conserved ID-associated missense mutations that disrupt KDM5’s transcriptional activity lead to the misexpression of genes required for MB morphology and cognitive function. This hypothesis will be tested in three specific aims. The first will be to quantify the extent of MB defects in all kdm5 mutant strains harboring ID- associated missense mutations at both gross and single-cell resolution. The second aim will define the gene expression defects within MB neurons of kdm5 knockdown and ID mutant strains using combined genome-wide transcriptome (RNA-seq) and binding (ChIP-seq) assays. Our third aim will quantify analogous cognitive and behavioral phenotypes that are classically associated with ID. This work will thus be the first to utilize conserved ID-causing KDM5 missense alleles to link ID-associated behavioral phenotypes with neuronal and transcriptional regulatory programs, opening new avenues for the development of therapeutic strategies. Under the mentorship and guidance of Drs. Julie Secombe and Nicholas Baker, I will be able to accomplish these goals while acquiring new skills in developmental neuroscience and related fields. Additionally, I will gain valuable experience presenting, networking, and preparing manuscripts, skills that are essential as I train to become an independent investigator and physician-scientist in the neurosciences.
摘要 智力残疾(ID)障碍影响2%的人口,其特征是智商得分低于 70人有适应功能缺陷超过400个基因的突变有助于ID的发病机制 疾病,患者表现出学习和记忆障碍,通常具有综合征特征, 癫痫焦虑身材矮小和攻击性倾向我们的研究集中在KDM 5家族, 转录调节因子,突变占遗传性ID的1-3%,从轻度到重度。的 KDM 5蛋白影响神经元功能的分子机制在很大程度上仍然未知, 没有有效治疗策略的患者。因此,本项目的首要目标是了解 KDM 5突变如何影响神经元和转录输出,从而影响认知。在这里,我们将 利用遗传上易处理的果蝇,其编码kdm 5的单一直系同源物,来研究神经元 携带患者源性KDM 5错义的果蝇的形态、转录产物和行为表型 突变。我们已经产生了一组10种果蝇品系,每一种都含有果蝇中的保守突变 kdm 5,其类似于ID相关等位基因。初步数据表明,RNAi介导的 kdm 5的敲低导致蘑菇体(MB)的深刻指导和生长缺陷,这是一个配对的 神经纤维是一种富含神经纤维的结构,是获得、巩固和恢复长期和短期记忆所必需的。 值得注意的是,在携带类似于ID-1突变的果蝇中观察到类似的形态学MB缺陷。 导致先前与KDM 5 DNA结合有关的富含A/T的相互作用结构域(ARID)中的错义突变。 基于这些和其他数据,我们的中心假设是KDM 5对MB的发展至关重要, 保守的ID相关错义突变破坏了KDM 5的转录活性, MB形态和认知功能所需的基因表达错误。这一假设将在 三个具体目标。第一个将是量化所有携带ID-1000的kdm 5突变株中MB缺陷的程度。 相关的错义突变在总和单细胞分辨率。第二个目标是定义基因 使用组合的全基因组技术检测kdm 5敲低和ID突变株的MB神经元内的表达缺陷 转录组(RNA-seq)和结合(ChIP-seq)测定。我们的第三个目标是量化类似的认知和 行为表型是经典的ID相关。这项工作将因此是第一次利用保守的 导致ID的KDM 5错义等位基因将ID相关的行为表型与神经元和转录因子联系起来 监管计划,为治疗策略的发展开辟了新的途径。在指导下 朱莉Secombe和尼古拉斯贝克的指导下,我将能够实现这些目标,同时获得 发展神经科学及相关领域的新技能。此外,我还将获得宝贵的经验 展示,网络,准备手稿,这些技能是我训练成为一个独立的 神经科学领域的研究者和医生科学家。

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Caregiver-reported characteristics of children diagnosed with pathogenic variants in KDM5C.
护理人员报告的被诊断患有 KDM5C 致病性变异的儿童的特征。
Molecular and cellular events linking variants in the histone demethylase KDM5C to the intellectual disability disorder Claes-Jensen syndrome.
  • DOI:
    10.1111/febs.16204
  • 发表时间:
    2022-12
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Hatch HAM;Secombe J
  • 通讯作者:
    Secombe J
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Hayden Alexander Moses Hatch其他文献

Hayden Alexander Moses Hatch的其他文献

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{{ truncateString('Hayden Alexander Moses Hatch', 18)}}的其他基金

Transcriptional regulation, neuronal development, and function of the mushroom body in a Drosophila model of intellectual disability
智力障碍果蝇模型中的转录调节、神经元发育和蘑菇体的功能
  • 批准号:
    10056231
  • 财政年份:
    2018
  • 资助金额:
    $ 5.18万
  • 项目类别:
Transcriptional regulation, neuronal development, and function of the mushroom body in a Drosophila model of intellectual disability
智力障碍果蝇模型中的转录调节、神经元发育和蘑菇体的功能
  • 批准号:
    9679001
  • 财政年份:
    2018
  • 资助金额:
    $ 5.18万
  • 项目类别:

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