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

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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.