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

基本信息

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
项目类别：
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

项目摘要

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.

我们发现三个转录因子ASCL1，MyT1样（MYT1L）和BRN2可以重新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测定因子。 ASCL1和BRN2 是研究良好的基因。另一方面，myt1l是一个相当未表征的锌指域蛋白质预测为转录因子。它具有非常独特的表达模式：它在几乎所有神经元，但同时也是神经元的特定的，据我们所知，唯一的转录已知的因素是特定的，同时是泛神经元。独立于重编程工作，最近的测序研究表明，MyT1L经常在神经精神疾病中突变自闭症和精神分裂症。然而，对这个基因知之甚少。甚至没有鼠标的淘汰因此，我们已经开始研究MyT1L在重编程中和正常情况下的作用发展。我们对其分子功能的第一个见解表明，myt1l对于神经元很重要重编程和正常的胚胎神经发生，主要通过非转录表示神经元谱系程序。该研究项目的目的是更好地了解MYT1L在神经发生中的作用已完成。我们建议使用其在分子，细胞回路和行为水平上的作用鼠标作为模型系统。我们拥有有趣的初步数据，大约三分之一的自闭症自闭症 - 引起染色质因子也是MYT1L的候选伴侣。这表明所有这些突变可能会收敛于假设的MYT1L相关的“染色质途径”，至少在自闭症子集。该项目将检验该假设，并评估是否干扰这种染色质“途径”可能会纠正由MyT1L缺失引起的分子，细胞或行为表型。由于修饰酶的染色质原则上是可以处理的，因此希望是此类染色质因子的功能干预可能是携带加速儿童的热值 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素可以挽救分子，细胞或行为MYT1L表型。

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）

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
作者：
通讯作者：

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
作者：
通讯作者：

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Thomas C. Sudhof其他文献

Single piconewton forces regulate dissociation of the Latrophilin-3 gain domain

DOI：
10.1016/j.bpj.2022.11.696
发表时间：
2023-02-10
期刊：
Conference abstract
影响因子：
作者：
Brian L. Zhong;Christina E. Lee;Vipul T. Vachharajani;Thomas C. Sudhof;Alexander R. Dunn
通讯作者：
Alexander R. Dunn