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Musashi1 and miR-137 antagonism: impact on neurogenesis and diseases

Musashi1 和 miR-137 拮抗：对神经发生和疾病的影响

基本信息

批准号：
10064506
负责人：
Erzsebet Kokovay
金额：
$ 42.48万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
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：
2020-09-30 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10064506
关键词：
Alzheimer&apos s Disease Biological Assay Biological Process Brain Brain Neoplasms Cell Cycle Cell Death Cell Differentiation process Cell Fate Control Cells Clustered Regularly Interspaced Short Palindromic Repeats Collecting Cell Complex Data Data Set Development Disease Ectopic Expression Equilibrium Expression Profiling Gene Expression Genes Genomics Glioblastoma Glioma Goals Hippocampus (Brain)In Vitro Infection Lead Maps Measures Memory Messenger RNA MicroRNAs Mitosis Mitotic Modeling Molecular Morphogenesis Morphology Mus Nature Nerve Degeneration Neurodegenerative Disorders Neuronal Differentiation Neurons Open Reading Frames Pattern Phenotype Physiological RNA-Binding Proteins Regulation Role Subfamily lentivirinae TAL1 gene Testing Therapeutic Therapeutic Intervention Transfection Translations adult neurogenesis base cancer cell cell motility differential expression experimental study gene repression genetic association genome-wide improved in vivo inhibitor/antagonist nervous system disorder neurogenesis novel therapeutics repaired ribosome profiling self-renewal single cell sequencing transcriptome sequencing tumor tumorigenesis

项目摘要

Adult neurogenesis is fundamental to brain function with important roles in memory and repair. During neurogenesis, dramatic physiological and morphological alterations take place due to coordinated changes in gene expression driven by specific regulators. Dysregulation can ultimately lead to reduced repair, neurodegenerative diseases and brain tumor development. We identified a molecular switch between self-renewal and differentiation having as central players Musashi1 and miR-137. These regulators have opposite expression patterns and functions. Musashi1 (Msi1) is a stem-cell protein implicated in self-renewal while miR-137 functions as a neurogenic miRNA. Msi1 and miR-137 interact at two different levels. First, miR-137 represses Msi1. Second, genomic analyses revealed that Msi1 and miR-137 regulate in opposite directions a large set of target genes implicated in cell migration, neuronal differentiation and cell morphogenesis. We propose that the balance between Msi1 and miR-137 is a key factor in cell fate decisions. In our antagonistic model, Msi1 promotes self-renewal mainly by increasing the expression of targets shared with miR-137 while miR-137 drives differentiation using a double negative switch, inhibiting Msi1 and also the their shared targets. In Aim 1, we will use genomic analyses to build an extended regulatory network for Msi1 and miR-137. We will establish connections (via regulatory, functional or genetic associations) between Msi1/miR-137 shared and unique targets to other genes displaying changes in expression during neurogenesis and identify other regulators that potentially function as partners of Msi1 and miR-137. In Aim 2, we will investigate two scenarios relevant to Alzheimer’s and glioblastoma development: 1) Msi1 inhibition is critical to miR-137 function in differentiation, 2) if miR-137 high expression is required to maintain the neuronal phenotype and 3) if an increase in Msi1 expression in differentiated cells could trigger cell cycle re-entry and repression of genes that maintain the neuronal phenotype. Next, to further support our model of antagonism, we will check if inhibition of miR-137 increases Msi1 expression in hippocampal neurons and if the alterations triggered by miR-137 inhibition can be “neutralized” by silencing Msi1.

成人神经发生是大脑功能的基础，在记忆和修复中起着重要作用。在