Glial HIFa: mechanisms and implications in hypoxia/ischemia-induced oligodendroglial pathology

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Glial HIFa: mechanisms and implications in hypoxia/ischemia-induced oligodendroglial pathology Preterm birth before 37th gestational week affects 1 of 10 infants and is an enormous burden on public health. Due to the immaturity of the respiratory system and the brain white matter vasculature of preterm infants, hypoxia/ischemia (H/I)-elicited diffuse white matter injury (WMI) frequently occurs in preterm brain. Disturbed myelination is a hallmark pathological feature in diffuse WMI. Impaired differentiation of myelin-producing oligodendrocytes from oligodendrocyte progenitor cells (referred to as OPC differentiation) is a primary culprit for disturbed myelination. No clinical therapies exist for promoting myelination in preterm infants affected by WMI. Therefore, studying molecular mechanisms underlying arrested OPC differentiation in WMI is important and instrumental in designing myelination therapies for treating hypomyelination in preterm infants. This project aims to define molecular mechanisms underlying the disturbed myelin formation in diffuse WMI with a focus on the function and mechanisms of glial HIFα in OPC differentiation and myelination. The developing central nervous system (CNS) is exposed to a physiologically hypoxic environment under which hypoxia inducible factor alpha, HIFα (HIF1α and HIF2α) is transiently stabilized to regulate neural development. The role of HIFα in glial cell development remains unknown until a seminal study reported a concept that oligodendroglial HIFα stabilization disturbed normal OPC differentiation through activating autocrine Wnt signaling (Yuen et al., 2014 Cell). However, our recent in vivo study (Zhang et al., 2020 Nature Communications) weakens the concept and unraveled a glial type-specific HIFα-Wnt regulation: oligodendroglial HIFα does not regulate Wnt signaling while astroglial HIFα surprisingly does. Our submitted study (Zhang et al., 2020 BioRxiv, doi:10.1101/2020.03.30.015131) further demonstrated an autocrine Wnt-independent role of HIFα in normal oligodendroglial development and discovered a novel HIFα target whose activation inhibits OPC differentiation. Going forward to WMI, we found persistent HIFα activation in glial cells and interestingly, dampening such HIFα activation mitigated myelination disturbance in an animal model for diffuse WMI. Built on these substantive data, we propose an overarching hypothesis that, under WMI, oligodendroglial HIFα regulates OPC differentiation in a manner independent of autocrine Wnt signaling as previously thought (tested in Aim 1), instead, through activating SOX9, a new non-canonical HIFα target we identified (tested in Aim 2) and that astrocytes control OPC differentiation through HIFα-activated paracrine Wnt signaling (tested in Aim 3). We will use glial type-specific and time-conditional genetic mutants and a preterm human brain-equivalent mouse model for diffuse WMI to test our hypothesis. This project will likely advance our fundamental mechanism knowledge of glial HIFα in oligodendroglial biology and pathology and provide new data into the therapeutic potential of glial HIFα in overcoming disturbed myelination in preterm infants affected by diffused WMI.