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The Role of Notch Signaling in Shh-mediated Oligodendrocyte Fate Specification

Notch 信号在 Shh 介导的少突胶质细胞命运规范中的作用

基本信息

批准号：
10751568
负责人：
Luuli Tran
金额：
$ 3.9万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10751568
关键词：
ATAC-seq Axon Brain Cells Central Nervous System Chromatin Competence Data Data Set Defect Demyelinations Development Disease Dorsal Embryo Embryonic Development Epigenetic Process Equilibrium Exposure to Functional disorder Gene Expression Genetic Transcription Injury Knowledge Lead Mediating Methods Modeling Molecular Multiple Sclerosis Mus Myelin Neocortex Nerve Degeneration Neuroglia Neurons Neurophysiology - biologic function Notch Signaling Pathway Oligodendroglia Pathology Pathway interactions Pattern Peripheral Positioning Attribute Production Prosencephalon Proteins Regulation Research Role SHH gene Signal Pathway Signal Transduction Sonic Hedgehog Pathway Specific qualifier value Spinal Cord System Testing Work cell fate specification cell type cognitive disability excitatory neuron extracellular genetic approach genetic manipulation in vivo insight leukodystrophy motor impairment myelination neocortical nerve stem cell nervous system disorder neural circuit neurogenesis notch protein novel novel therapeutic intervention oligodendrocyte lineage oligodendrocyte precursor pharmacologic precursor cell progenitor response single cell analysis single-cell RNA sequencing smoothened signaling pathway tool transcription factor

项目摘要

PROJECT SUMMARY Oligodendrocytes are glial cells in the central nervous system that form myelin, which are critical for the proper formation and function of neural circuits. During brain development, neural progenitor cells first give rise to excitatory neurons before gradually transitioning to the production of oligodendrocyte precursor cells (OPCs); a phenomenon known as the “neuron-glia switch”. Whereas oligodendrocyte differentiation from OPCs and myelin formation are well understood, we still do not know the earlier mechanisms that facilitate the neuron-glia switch and specify progenitors towards an OPC fate. This study aims to understand the developmental and molecular mechanisms that instruct neural progenitors to generate OPCs instead of neurons in the developing mouse neocortex. Our lab previously identified Sonic hedgehog (Shh) as a critical extracellular signal that initiates the neuron-glia switch during late embryonic development. However, while some progenitors generate OPCs in response to Shh, others continue to produce neurons. This suggests that co-existing neural progenitors differentially respond to Shh and require additional cell-intrinsic mechanisms to acquire an OPC fate. Our single cell RNA-sequencing analysis and my preliminary data indicate that both the Notch signaling pathway and the transcription factor Ascl1 are critical for promoting OPC specification from neural progenitors in response to Shh. Importantly, Ascl1 has recently been identified as a pioneer transcription factor capable of promoting chromatin accessibility to direct cell fates. Based on these data, I hypothesize that the Notch signaling pathway promotes OPC specification by regulating the response of neural progenitors to Shh in addition to establishing an epigenetic state primed for the OPC fate through Ascl1. I will test this hypothesis in two Specific Aims: 1) Define the functional role of Notch signaling in Shh-mediated OPC specification using in vivo genetic manipulations and ex vivo pharmacological approaches and 2) Test the hypothesis that Notch signaling cooperates with Ascl1 to promote an epigenetic state for specifying the oligodendrocyte lineage. Completion of these aims will significantly contribute to a better understanding of neural cell fate specification and oligodendrocyte development, which will allow for novel tools and methods to restore myelin following disease and injury.

项目总结