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: 10579921
• 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/10579921
• 关键词: Acute; Adult; Affect; Anxiety; Behavior assessment; Behavioral; Behavioral Assay; Binding; Binding Proteins; Biological Assay; Biological Models; Brain; Brain region; Categories; Chromatin; Classification; Communication; Data; Development; Embryo; Enzymes; Family member; Fibroblasts; Foundations; Functional disorder; Gene Expression Regulation; Gene Family; Genes; Genetic Epistasis; Genetic Transcription; Genomics; Goals; Heterozygote; In Situ; Intervention; Knockout Mice; Learning; Link; Mass Spectrum Analysis; Mediating; Memory; Molecular; Morphology; Motivation; Motor; Mus; Mutate; Mutation; Neurodevelopmental Disorder; Neurons; Pathway interactions; Patients; Pattern; Performance; Phenotype; Probability; Property; Proteins; Publishing; Regulatory Pathway; Reporting; Research; Research Project Grants; Research Proposals; Role; Schizophrenia; Site; Slice; Social Interaction; Sorting; 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; pharmacologic; postmitotic; 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(Myt1)和Brn2可以对成纤维细胞进行重新编程 直接转化为功能神经元，因此是强大的神经元谱系决定因素。ASCL1和Brn2 都是经过充分研究的基因。另一方面，Myt1l是一个相当未知的锌指结构域，包含 被预测为转录因子的蛋白质。它有一个非常独特的表达模式：它在 几乎所有神经元，但同时也是神经元特有的，据我们所知，唯一的转录 已知的因子同时具有特异性和泛神经性。与重新编程工作无关， 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，人们对这种基因知之甚少。即使是击倒老鼠的人也没有 已经被报道过了。因此，我们已经开始研究Myt1l在重新编程和正常情况下的作用 发展。我们对Myt1分子功能的初步了解表明Myt1对神经元很重要 重编程与正常胚胎神经发生主要通过转录抑制非- 神经元谱系计划。 这项研究项目的目的是更好地了解Myt1在神经发生后神经元中的作用 已经完成了。我们建议研究它在分子、细胞回路和行为水平上的作用 以鼠标为模型系统。我们有耐人寻味的初步数据，大约三分之一的高自信自闭症患者- 导致染色质因子也是Myt1l的候选结合伙伴。这表明所有这些突变 可能会聚在一条假设的与Myt11相关的“染色质途径”上，这条途径至少在功能上是不正常的。 自闭症的子集。该项目将检验这一假设，并评估是否干扰了 这条染色质“途径”可能纠正Myt1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上是容易处理的，因此希望一种 对这些染色质因子的功能干预可能对携带 Myt11突变。因此，我们将在我们的三个目标中测试这些染色质的操纵 因子可以挽救分子、细胞或行为Myt1表型。

项目成果

Myt1l haploinsufficiency leads to obesity and multifaceted behavioral alterations in mice.

• DOI: 10.1186/s13229-022-00497-3
• 发表时间: 2022-05-10
• 期刊: Molecular autism
• 影响因子: 6.2

Persistent transcriptional programmes are associated with remote memory.

• DOI: 10.1038/s41586-020-2905-5
• 发表时间: 2020-11
• 期刊: Nature
• 影响因子: 64.8