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

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Principal Investigator: Luuli  Tran
Organization: UNIVERSITY OF COLORADO DENVER
Fiscal Year: 2024
Award: $40,313
Funding agency: National Institute of Neurological Disorders and Stroke

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.

Terms: <ATAC sequencing><ATAC-seq><ATACseq><Assay for Transposase-Accessible Chromatin using sequencing><Axon><Basal Transcription Factor><Basal transcription factor genes><Brain><Brain Nervous System><CNS Nervous System><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Central Nervous System><Chromatin><Competence><Data><Data Set><Defect><Demyelinations><Development><Disease><Disorder><Disseminated Sclerosis><Dorsal><Dysfunction><Embryo><Embryo Development><Embryogenesis><Embryonic><Embryonic Development><Encephalon><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Equilibrium><Exposure to><Fore-Brain><Forebrain><Functional disorder><Gene Expression><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genetic Transcription><Glia><Glial Cells><Hedgehog (Hh) signal transduction pathway><Injury><Intracellular Communication and Signaling><Knowledge><Kolliker's reticulum><Lead><Mediating><Medulla Spinalis><Methods><Mice><Mice Mammals><Modeling><Molecular><Multiple Sclerosis><Murine><Mus><Myelin><Neocortex><Nerve Cells><Nerve Degeneration><Nerve Unit><Nervous System Diseases><Nervous System Disorder><Neural Cell><Neural Stem Cell><Neuraxis><Neurocyte><Neuroglia><Neuroglial Cells><Neurologic Disorders><Neurological Disorders><Neuron Degeneration><Neurons><Neurophysiology - biologic function><Non-neuronal cell><Nonneuronal cell><Notch Signaling Pathway><Oligodendrocytes><Oligodendrocytus><Oligodendroglia><Oligodendroglia Cell><Pathology><Pathway interactions><Pattern><Pb element><Peripheral><Physiopathology><Position><Positioning Attribute><Production><Prosencephalon><Proteins><Proteolysis and Signaling Pathway of Notch><RNA Expression><Regulation><Research><Role><SHH><SHH gene><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Sonic Hedgehog><Sonic Hedgehog (Shh) Pathway><Sonic Hedgehog Pathway><Specific qualifier value><Specified><Spinal Cord><System><Testing><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Work><assay for transposase accessible chromatin followed by sequencing><assay for transposase accessible chromatin seq><assay for transposase accessible chromatin sequencing><assay for transposase-accessible chromatin with sequencing><balance><balance function><biological signal transduction><cell fate specification><cell type><cognitive disability><cognitively disabled><demyelinate><developmental><epigenetically><excitatory neuron><extracellular><gene manipulation><genetic approach><genetic manipulation><genetic strategy><genetically manipulate><genetically perturb><heavy metal Pb><heavy metal lead><hedgehog signaling><hedgehog signaling pathway><hh signaling pathway><homotypical cortex><in vivo><injuries><insight><insular sclerosis><isocortex><leukodystrophy><motor impairment><movement impairment><movement limitation><myelination><neocortical><neopallium><nerve cement><nerve stem cell><neural circuit><neural circuitry><neural degeneration><neural function><neural precursor><neural precursor cell><neural progenitor><neural progenitor cells><neurocircuitry><neurodegeneration><neurodegenerative><neurogenesis><neurological degeneration><neurological disease><neuron progenitors><neuronal><neuronal degeneration><neuronal progenitor><neuronal progenitor cells><neuronal stem cells><neuroprogenitor><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><notch><notch protein><notch receptors><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><oligodendrocyte lineage><oligodendrocyte precursor><oligodendrocyte progenitor><oligodendrocyte stem cell><pathophysiology><pathway><pharmacologic><precursor cell><progenitor><progenitor cell fate specification><progenitor fate specification><progenitor specification><response><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell analysis><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><smoothened signaling pathway><social role><stem cell fate specification><stem cell specification><synaptic circuit><synaptic circuitry><tool><transcription factor>