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样（Myt1l）和Brn2可以重编程成纤维细胞

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