Non-Canonical Targets of HIF1a Drive Cell-Type-Specific Dysfunction

Allan, Kevin; Hu, Lucille R.; Morton, Andrew; Scavuzzo, Marissa A.; Gevorgyan, Artur S.; Clayton, Benjamin L.L.; Bederman, Ilya; Hung, Stevephen; Bartels, Cynthia F.; Madhavan, Mayur; Tesar, Paul J.

doi:10.1101/2020.04.03.003632

Cited by 4 publications

(2 citation statements)

References 84 publications

(106 reference statements)

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“…The embryonic vasculature is subsequently remodeled at neonatal stages by neuronal and glial populations (Bozoyan et al, 2012;Harb et al, 2013;Ma et al, 2013;Paredes et al, 2018;Segarra et al, 2018;Vasudevan et al, 2008), including NG2 glia (Minocha et al, 2015). Several studies show that OPC-encoded HIF function regulates cellautonomous OPC maturation and myelination as well as WM angiogenesis via paracrine signaling (Allan et al, 2020;Yuen et al, 2014;Zhang et al, 2020). Here, we extend insights into this process and show the OPCs and BVs engage in further cell-cell interactions in the neonatal brain.…”

Section: Discussionsupporting

confidence: 52%

Wnt-Dependent Oligodendroglial-Endothelial Interactions Regulate White Matter Vascularization and Attenuate Injury

Chavali

Ulloa-Navas

Pérez-Borredá

et al. 2020

Neuron

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Section: Discussionsupporting

confidence: 52%

Wnt-Dependent Oligodendroglial-Endothelial Interactions Regulate White Matter Vascularization and Attenuate Injury

Chavali

Ulloa-Navas

Pérez-Borredá

et al. 2020

Neuron

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“…A recent publication has demonstrated that chronic HIF-1a accumulation in pluripotent stem cell-derived oligodendrocyte progenitors blocked differentiation. Inhibition of HIF-1 signaling restored oligodendrocyte formation even in partially hypoxic human oligocortical spheroids (62). Both observations fit well with the theory that demyelinated axons that are electrically intact with properly firing neurons provide an increased likelihood for remyelination [reviewed in (63,64)].…”

Section: Discussionsupporting

confidence: 77%

Acriflavine, a HIF-1 inhibitor, preserves vision in an experimental autoimmune encephalomyelitis model of optic neuritis

Anders,

Elwood,

Kardon

et al. 2023

Front. Immunol.

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IntroductionOptic neuritis (ON) is often an early sign of multiple sclerosis (MS), and recent studies show a link between HIF-1 pathway activation and inflammation. This study aimed to determine if inhibition of the HIF-1 pathway using the HIF-1a antagonist acriflavine (ACF) can reduce clinical progression and rescue the ocular phenotype in an experimental autoimmune encephalomyelitis (EAE) ON model.MethodsEAE-related ON was induced in 60 female C57BL/6J mice by immunization with MOG33-55, and 20 EAE mice received daily systemic injections of ACF at 5 mg/kg. Changes in the visual function and structure of ACF-treated EAE mice were compared to those of placebo-injected EAE mice and naïve control mice.ResultsACF treatment improved motor–sensory impairment along with preserving visual acuity and optic nerve function. Analysis of retinal ganglion cell complex alsoshowed preserved thickness correlating with increased survival of retinal ganglion cells and their axons. Optic nerve cell infiltration and magnitude of demyelination were decreased in ACF-treated EAE mice. Subsequent in vitro studies revealed improvements not only attributed to the inhibition of HIF-1 butalso to previously unappreciated interaction with the eIF2a/ATF4 axis in the unfolded protein response pathway.DiscussionThis study suggests that ACF treatment is effective in an animal model of MS via its pleiotropic effects on the inhibition of HIF-1 and UPR signaling, and it may be a viable approach to promote rehabilitation in MS.

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HIFα regulates developmental myelination independent of autocrine Wnt signaling

Zhang

Wang

et al. 2020

Preprint

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words)The developing CNS is exposed to physiological hypoxia, under which hypoxia inducible factor alpha (HIFα) is stabilized and plays a crucial role in regulating neural development. The cellular and molecular mechanism of HIFα in developmental myelination remain incompletely understood. Previous concept proposes that HIFα regulates CNS developmental myelination by activating the autocrine Wnt/β-catenin signaling in oligodendrocyte progenitor cells (OPCs).Here, by analyzing a battery of genetic mice of both sexes, we presented in vivo evidence supporting an alternative understanding of oligodendroglial HIFα-regulated developmental myelination. At the cellular level, we found that HIFα was required for developmental myelination by transiently controlling upstream OPC differentiation but not downstream oligodendrocyte maturation and that HIFα dysregulation in OPCs but not oligodendrocytes disturbed normal developmental myelination. We demonstrated that HIFα played a minor, if any, role in regulating canonical Wnt signaling in the oligodendroglial lineage or in the CNS. At the molecular level, blocking the autocrine Wnt signaling did not affect HIFα-regulated OPC differentiation and myelination. We further identified HIFα-Sox9 regulatory axis as an underlying molecular mechanism in HIFα-regulated OPC differentiation. Our findings support a concept shift in our mechanistic understanding of HIFα-regulated CNS myelination from the previous Wnt-dependent view to a Wnt-independent one and unveil a previously unappreciated HIFα-Sox9 pathway in regulating OPC differentiation. Significant statement (100 words)Promoting disturbed developmental myelination is a promising option in treating periventricular leukomalacia, a major form of brain white matter injury affecting premature infants. In the developing CNS, HIFα is a master regulator that adapts neural cells to physiological and pathological hypoxic cues. The role and mechanism of HIFα in oligodendroglial myelination, which is developmentally disturbed in preterm infants affected with 3 periventricular leukomalacia, are incompletely understood. Our findings presented here represent a concept shift in our mechanistic understanding of HIFα-regulated developmental myelination and suggest the potential of intervening oligodendroglial HIFα-mediated signaling pathway in mitigating disturbed myelination in premature white matter injury.

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Non-Canonical Targets of HIF1a Drive Cell-Type-Specific Dysfunction

Cited by 4 publications

References 84 publications

Wnt-Dependent Oligodendroglial-Endothelial Interactions Regulate White Matter Vascularization and Attenuate Injury

Wnt-Dependent Oligodendroglial-Endothelial Interactions Regulate White Matter Vascularization and Attenuate Injury

Acriflavine, a HIF-1 inhibitor, preserves vision in an experimental autoimmune encephalomyelitis model of optic neuritis

HIFα regulates developmental myelination independent of autocrine Wnt signaling

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