The role of Myt1l in the developing and adult mouse brain

Myt1l 在发育中和成年小鼠大脑中的作用

• 批准号: 10333320
• 负责人: Thomas C. Sudhof
• 金额: $ 69.82万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10333320
• 关键词: Acute; Adult; Affect; Anxiety; Behavioral; Behavioral Assay; Binding; Binding Proteins; Biological Assay; Biological Models; Brain; Brain region; Categories; Chromatin; Communication; Data; Development; Disease; Embryo; Enzymes; Family member; Fibroblasts; Foundations; Functional disorder; Gene Expression Regulation; Gene Family; Genes; Genetic Epistasis; Genomics; Goals; In Situ; Intervention; Knockout Mice; Learning; Link; Mass Spectrum Analysis; Mediating; Memory; Molecular; Morphology; Motivation; Motor; Mus; Mutate; Mutation; Neurons; Pathway interactions; Patients; Pattern; Performance; Pharmacology; Phenotype; Property; Proteins; Publishing; Regulatory Pathway; Reporting; Research; Research Project Grants; Research Proposals; Role; Schizophrenia; Site; Slice; Social Interaction; Sorting - Cell Movement; Synapses; Testing; Therapeutic; Time; Work; Zinc Fingers; autism spectrum disorder; autistic children; behavioral phenotyping; experimental study; falls; functional group; gene repression; in vivo; insight; knock-down; loss of function; member; neurogenesis; neuropsychiatric disorder; postnatal; programs; recruit; small hairpin RNA; synaptic function; transcription factor; transcriptome; virtual

We found that the three transcription factors Ascl1, Myt1-like (Myt1l), and Brn2 can reprogram fibroblasts directly into functional neurons and are thus powerful neuronal lineage determination factors. Ascl1 and Brn2 are well studied genes. Myt1l on the other hand is a fairly uncharacterized zinc finger domain containting protein predicted to be a transcription factor. It has a remarkably unique expression pattern: it is expressed in virtually all neurons, but at the same time is also specific for neurons, to our knowledge the only transcription factor known to be specific and pan-neuronal at the same time. Independent of the reprogramming work, recent sequencing studies showed that MYT1L is frequently mutated in neuropsychiatric disease including autism and schizophrenia. Nevertheless, very little is known about this gene. Not even a mouse knock-out has been reported yet. We have therefore begun to investigate Myt1l's role in reprogramming and during normal development. Our first insights about its molecular function suggest that Myt1l is important for neuronal reprogramming and normal embryonic neurogenesis acting predominantly by transcriptional repression of non- neuronal lineage programs. The goal of this research project is to better understand the role of Myt1l in neurons after neurogenesis is completed. We propose to investigate its role on the molecular, cellular circuit, and behavioral level using the mouse as model system. We have intriguing preliminary data that about a third of high confidence autism- causing chromatin factors are also candidate binding partners of Myt1l. This suggests that all these mutations might converge on a hypothetical Myt1l-associated “chromatin pathway” which is dysfunctional in at least subset of autism. This project will test this hypothesis and evaluate whether interference with the members of this chromatin “pathway” might rectify molecular, cellular or behavioral phenotypes caused by Myt1l deletion. Since chromatin modifying enzymes are in principle pharmacologically tractable the hope would be that a functional intervention of such chromatin factors may be of therapeutic value for autistic children carrying MYT1L mutations. We will therefore test throughout all our three aims whether manipulation of these chromatin factors can rescue the molecular, cellular, or behavioral Myt1l phenotypes.

我们发现三种转录因子 Ascl1、Myt1-like (Myt1l) 和 Brn2 可以对成纤维细胞进行重编程 直接进入功能神经元，因此是强大的神经元谱系决定因素。 Ascl1 和 Brn2 是经过充分研究的基因。另一方面，Myt1l 是一个相当未表征的锌指结构域，包含 预测为转录因子的蛋白质。它有一个非常独特的表达模式：它的表达方式是 几乎所有神经元，但同时也是神经元特有的，据我们所知，这是唯一的转录 已知同时具有特异性和泛神经元的因子。独立于重新编程工作， 最近的测序研究表明，MYT1L 在神经精神疾病中经常发生突变，包括 自闭症和精神分裂症。然而，人们对这个基因知之甚少。甚至连鼠标敲除都没有 尚未被报道。因此，我们开始研究 Myt1l 在重编程和正常过程中的作用 发展。我们对其分子功能的初步了解表明 Myt1l 对神经元很重要 重编程和正常胚胎神经发生主要通过非-转录抑制作用 神经元谱系程序。 该研究项目的目标是更好地了解 Myt1l 在神经发生后神经元中的作用 已完成。我们建议使用以下方法研究其在分子、细胞回路和行为水平上的作用 鼠标作为模型系统。我们有有趣的初步数据表明，大约三分之一的高置信度自闭症患者—— 引起染色质的因子也是 Myt1l 的候选结合伴侣。这表明所有这些突变 可能会集中在一个假设的 Myt1l 相关“染色质途径”上，该途径至少在功能失调 自闭症的一个子集。该项目将测试这一假设并评估是否对成员进行干扰 该染色质“途径”可能会纠正由 Myt1l 缺失引起的分子、细胞或行为表型。 由于染色质修饰酶原则上在药理学上是易于处理的，因此希望 此类染色质因子的功能干预可能对携带病毒的自闭症儿童具有治疗价值 MYT1L 突变。因此，我们将在所有三个目标中测试是否操纵这些染色质 因子可以挽救分子、细胞或行为 Myt1l 表型。