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Ascl 1、Myt 1-like（Myt 1 l）和Brn 2可以重编程成纤维细胞， 直接进入功能性神经元，因此是强大的神经元谱系决定因子。Ascl 1和Brn 2 都是经过充分研究的基因另一方面，Myt 1 l是一个相当未表征的锌指结构域， 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： 几乎所有的神经元，但同时也是特定的神经元，据我们所知，唯一的转录 已知是特异性和泛神经元的因子。独立于重编程工作， 最近的测序研究表明，MYT 1 L在神经精神疾病中经常发生突变， 自闭症和精神分裂症。然而，人们对这个基因知之甚少。即使是敲除老鼠 已经被报道了。因此，我们已经开始研究Myt 1 l在重编程和正常发育过程中的作用。 发展我们对Myt 1 l分子功能的初步了解表明，Myt 1 l对神经元细胞的生长和分化非常重要。 重编程和正常胚胎神经发生主要通过转录抑制非- 神经元谱系程序。 该研究项目的目标是更好地了解Myt 1 l在神经发生后神经元中的作用 完成了我们建议使用分子水平、细胞回路和行为水平来研究它的作用。 小鼠作为模型系统。我们有有趣的初步数据，大约三分之一的高自信自闭症- 引起染色质的因子也是Myt 11的候选结合配偶体。这表明所有这些突变 可能会聚集在一个假设的Myt 1 l相关的“染色质途径”，这是功能失调，至少在 自闭症的一个子集本项目将测试这一假设，并评估是否干扰的成员， 这种染色质“途径”可能会纠正由Myt 11缺失引起的分子、细胞或行为表型。 由于染色质修饰酶在原则上是易处理的， 这些染色质因子的功能干预可能对自闭症儿童具有治疗价值， MYT 1 L突变。因此，我们将在我们所有的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Myt 1 l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