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Modulating Oligodendrocyte Formation in Health and Disease

Allan, Kevin Cameron
http://rave.ohiolink.edu/etdc/view?acc_num=case1624552992203166

Abstract Details

2021, Doctor of Philosophy, Case Western Reserve University, Genetics.
Interrogating how somatic stem cells interpret and transmit the intricate web of extracellular and intracellular signals that regulate cell state is foundational to biology and informs regenerative medicine approaches for treating disease. Oligodendrocyte progenitor cells (OPCs) are stem cells in the developing and adult brain that form oligodendrocytes, which are responsible for myelinating and supporting neuronal axons. Here, we elucidate transcriptional regulators of the oligodendrocyte lineage in both physiologic and pathologic contexts to identify strategies for promoting myelin regeneration in disease. Oligodendrocyte formation follows a multi-step process of OPC differentiation into immature oligodendrocytes, followed by subsequent maturation to myelinating oligodendrocytes. The transcriptional regulators of oligodendrocyte maturation remain unknown. Here, we discovered that the transcription factor Sox6 forms developmental condensates across gene bodies in immature oligodendrocytes to stabilize this intermediate state. Loss of Sox6 prevented condensate gene activation and accelerated maturation of OPCs directly to myelinating oligodendrocytes. This work offers a novel approach to regenerate myelinating oligodendrocytes in disease. This multi-step differentiation process is impaired by low oxygen (hypoxia) as seen in stroke, premature birth, and respiratory distress syndromes. Foundational to the hypoxic response is the accumulation of evolutionarily conserved transcription factors called hypoxia-inducible factors (HIFs). While HIFs are transiently protective, chronic HIF accumulation drives distinct pathological responses in numerous tissues and exerts a powerful influence over cell fate decisions in a multitude of stem cell types, including impairing oligodendrocyte formation from OPCs. In this study, we demonstrate that non-canonical, cell-type-specific targets of HIF1a are sufficient to impair the expression of Sox10, which is required for oligodendrocyte formation. Screening a library of bioactive small molecules, we determined that inhibition of MEK/ERK signaling subverted the multi-faceted block in oligodendrocyte formation by driving Sox10 expression. This work uncovers potential nodes of intervention to reverse myelin damage in hypoxic disease and highlights the potential for HIF to interact with cell-type-specific transcriptional machinery to exert pleiotropic effects in diverse tissues. Collectively, these studies establish that transcriptional networks form biomolecular condensates to govern stem cell maturation and poise stem cells to respond to external stimuli in a cell-type-specific manner.
Paul Tesar, PhD (Advisor)
Drew Adams, PhD (Committee Chair)
Tara DeSilva, PhD (Committee Member)
Anthony Wynshaw-Boris, MD/PhD (Committee Member)
240 p.
Genetics; Neurosciences
Glia biology; oligodendrocytes; hypoxia; transcriptional condensates; molecular genetics; stem cell biology

Recommended Citations

Citations

  • Allan, K. C. (2021). Modulating Oligodendrocyte Formation in Health and Disease [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1624552992203166

    APA Style (7th edition)

  • Allan, Kevin. Modulating Oligodendrocyte Formation in Health and Disease . 2021. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1624552992203166.

    MLA Style (8th edition)

  • Allan, Kevin. "Modulating Oligodendrocyte Formation in Health and Disease ." Doctoral dissertation, Case Western Reserve University, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=case1624552992203166

    Chicago Manual of Style (17th edition)

case1624552992203166
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© 2021, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.
Release 3.2.12