权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Molecular mechanisms of motor neuron terminal identity

运动神经元末梢识别的分子机制

基本信息

批准号：
10183355
负责人：
Paschalis Kratsios
金额：
$ 30.07万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10183355
关键词：
Activator Appliances Adult Amyotrophic Lateral Sclerosis Animal Model Auxins Basic Science Binding Binding Sites Biological Models Brain Stem CRISPR/Cas technology Caenorhabditis elegans Cell Adhesion Molecules Cells Chromatin Chromatin Remodeling Factor Code Data Defect Development Developmental Delay Disorders Diagnosis Disease Ectopic Expression Embryo Ensure Etiology Event Genes Genetic Models Genetic Screening Genetic Transcription Goals Human Human Pathology Individual Ion Channel Lead Life Light Locomotion Maintenance Methods Molecular Molecular Mechanisms of Action Morphology Motor Motor Neuron Disease Motor Neurons Mus Mutate Mutation Nematoda Nerve Nervous system structure Neurons Neuropeptides Neurotransmitter Receptor Orthologous Gene Outcome Predisposition Property Proteins Regulator Genes Research Role Secure Spinal Spinal Cord Spinal Muscular Atrophy Syndrome System Testing Transcriptional Regulation cell type cholinergic chromatin immunoprecipitation differential expression effective therapy experimental study fly genome-wide insight knock-down motor control motor neuron development motor neuron function prevent receptor tool transcription factor transcriptome sequencing

项目摘要

Defects in motor neuron (MN) function or survival result in severe human pathologies, such as amyotrophic lateral sclerosis and spinal muscular atrophy, with distinct MN subtypes differing in susceptibility to disease. There is currently no effective treatment for MN disorders in part due to a lack of understanding of the molecular mechanisms that allow distinct MN subtypes to acquire and maintain their function-defining properties. Thus, basic research in model organisms such as nematodes, flies, and mice is needed to reveal such mechanisms. MN subtype function is endowed by the differential expression of terminal identity genes. Such genes encode proteins (e.g., ion channels, neurotransmitter receptors, neuropeptides, trans-membrane receptors, adhesion molecules) that are expressed continuously, from the last steps of development through adulthood, and thereby define the unique functional features of a given MN subtype. Hence, revealing the molecular mechanisms that induce (during development) and maintain (throughout life) expression of terminal identity genes will help us understand how MNs become and remain functional, a key goal in the fields of MN development and disease. A remarkable wealth of terminal identity markers is available for all cholinergic MN subtypes of the C. elegans nerve cord that control locomotion, providing a unique model system to elucidate how MNs acquire and maintain their functional features. Leveraging these tools, we discovered that the conserved Collier/Olf/Ebf-type transcription factor (TF) UNC-3 is required for the continuous function of all these cholinergic MN subtypes, and that this outcome arises from UNC-3-dependent induction and maintenance of MN subtype-specific terminal identity genes. Through unbiased genetic screens, we recently identified several conserved regulatory factors (6 TFs, 2 chromatin factors) that control the terminal identity of individual MN subtypes. Intriguingly, our preliminary results suggest that while UNC-3 activates expression of all MN subtype-specific terminal identity genes, these regulatory factors counteract the activator function of UNC-3 by repressing UNC-3 targets in specific MN subtypes. These observations suggest a general principle for the control of MN terminal identity, in which the transcriptional targets of a broadly acting activator (UNC-3) are repressed in a MN subtype-specific fashion by distinct TFs and chromatin factors. To test this hypothesis within the 5-year R01 timeframe, this proposal will focus on one TF (BNC-1/mammalian BNC1-2) and one chromatin factor (PBRM-1/mammalian BAF180) that counteract UNC-3 in different MN subtypes. Specifically, we seek to: (a) determine whether these two factors are required throughout life to secure subtype identity (Aim 1), (b) define the mechanism underlying the repressor activity of BNC-1 (Aim 2), and (c) decipher the function of PBRM-1 by identifying its downstream targets (Aim 3). The proposed experiments will establish a paradigm for induction and maintenance of MN terminal identity in a genetic model system, which could serve as a valuable entry point to understand how mammalian MNs become and remain functional.

运动神经元（MN）功能或存活的缺陷导致严重的人类病理，如肌萎缩症