Distinct modes of gene expression by KDM5

摘要 转录调节因子赖氨酸去甲基酶5(KDM5)家族的突变在慢性阻塞性肺疾病患者中被发现 智力障碍(ID)，表现为认知障碍，从轻度(智商50-70)到严重(智商30)不等。 然而，KDM5蛋白影响神经元发育和功能的分子机制仍然存在。 未知，留下了很大的知识缺口，阻碍了对受影响的潜在治疗方法的确定 病人。因此，我们研究的长期目标是在分子水平上确定KDM5如何调控基因 神经元发育和功能所必需的表达模式。我们将使用果蝇来实现这一点 因为它是用来定义人类神经发育的分子基础的已建立的模式生物 精神错乱。这里描述的研究使用了基因工具、细胞生物学分析和 认知行为学方法研究KDM5‘S基因在不同发育阶段神经细胞中的调控活性 发展。除了利用新产生的kdm5零等位基因和 细胞类型特异的可诱导RNAi介导的基因敲除试验，我们已经产生了一组8个果蝇菌株，每个菌株 其中在果蝇kdm5中含有类似于人类ID等位基因的突变。这种方法是可能的。 因为所有与疾病相关的突变都发生在进化上保守的氨基酸中。使用以下工具生成的数据 这些工具引导我们提出了一个中心假设，即KDM5调节对 神经元的发育和功能，这是受与智力相关的错义突变的影响 残疾。这一假设将在三个具体目标上得到检验。第一个目标是解决KDM5在成人中的作用 通过确定KDM5激活核糖体蛋白(RP)基因的机制来发挥大脑功能 翻译在学习和记忆中起着进化保守的作用。第二个目标集中在角色上 通过确定KDM5在幼虫神经元干中的作用机制，研究KDM5在发育过程中的作用 细胞(神经母细胞)，以促进学习和指导所需神经元的后续生长和指导 记忆。第三个目标定义了KDM5对学习和记忆的时间和空间要求。这 这项工作意义重大，因为我们将定义KDM5调节基因的新机制，这些机制对 神经元的发育和活动除了提供对 神经发育障碍。

Abstract Mutations in the lysine demethylase 5 (KDM5) family of transcriptional regulators are found in patients with intellectual disabilities (ID) that show cognitive impairment ranging from mild (IQ 50-70) to severe (IQ < 30). However, the molecular mechanisms by which KDM5 proteins impact neuronal development and function remain unknown, leaving a large knowledge gap and preventing the identification of potential treatments for affected patients. Thus, the long-term goal of our research is to define at the molecular level how KDM5 regulates gene expression patterns necessary for neuronal development and function. We will achieve this using Drosophila because it is an established model organism used to define the molecular basis of human neurodevelopmental disorders. Studies described here use a powerful combination of genetic tools, cell biological analyses and cognitive behavioral assays to dissect KDM5’s gene regulatory activities in neuronal cells at distinct stages of development. In addition to classical loss of function analyses utilizing a newly generated kdm5 null allele and cell type specific inducible RNAi-mediated knockdown assays, we have generated a set of eight fly strains, each of which harbors a mutation in Drosophila kdm5 analogous to a human ID allele. This approach is possible because all disease-associated mutations occur in evolutionarily conserved amino acids. Data generated using these tools lead us to propose the central hypothesis that KDM5 regulates the expression of genes essential for neuronal development and function, and that this is affected by missense mutations associated with intellectual disability. This hypothesis will be tested in three specific aims. The first aim addresses the role of KDM5 in adult brain function by defining the mechanism by which KDM5 activates ribosomal protein (Rp) genes, as de novo translation has an evolutionarily conserved role in learning and memory. The second aim focusses on the role of KDM5 during development by determining the mechanism by which KDM5 functions in larval neuronal stem cells (neuroblasts) to facilitate the subsequent growth and guidance of the neurons required for learning and memory. The third aim defines the temporal and spatial requirements of KDM5 for learning and memory. This work is significant because we will define new mechanisms of gene regulation by KDM5 that are critical for neuronal development and activity in addition to providing insight into the underlying causes of neurodevelopmental disorders.