KLF6 and STAT3 co-occupy regulatory DNA and functionally synergize to promote axon growth in CNS neurons

Wang, Zimei; Mehra, Vatsal; Simpson, Matthew T.; Maunze, Brian; Chakraborty, Advaita; Holan, Lyndsey; Eastwood, Erik; Blackmore, Murray G.; Venkatesh, Ishwariya

doi:10.1038/s41598-018-31101-5

Cited by 41 publications

(66 citation statements)

References 77 publications

(105 reference statements)

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“…2A,B). In contrast to prior findings (22), KLF6treated animals displayed only a non-significant trend toward enhanced CST growth in this injury paradigm (Supp. Fig.…”

Section: Resultscontrasting

confidence: 99%

“…These data indicate that when confronted with a deeper and more severe injury, KLF6stimulated axons are largely unable to regenerate, a finding reminiscent of prior findings with closely related KLF7 (21,23). Thus, although KLF-based manipulations elevate intrinsic regenerative ability in CST axons (22), extrinsic barriers continue to constrain growth.…”

Section: Resultssupporting

confidence: 65%

“…KLF6 is a pro-regenerative transcription factor that is expressed by corticospinal tract (CST) neurons during periods of axon growth, and then downregulated with maturation (22,24). We showed previously that forced re-expression of KLF6 in adult CST neurons enhances compensatory CST sprouting and regenerative growth after partial spinal injuries (22). Importantly, however, this KLF6-stimulated growth occurred through spared grey matter.…”

Section: Resultsmentioning

confidence: 99%

“…KLF factors comprise a 17-member family that play widespread roles in development, including both positive and negative regulation of axon growth (24,43). KLF6 and the closely related KLF7 stand out as the only members known to be pro-regenerative (21,22,24). In contrast to KLF7, which required addition of a VP16 transcriptional activation domain to evoke CST regeneration (21), KLF6 effectively promotes CST axon growth in its wild type form (22).…”

Section: Discussionmentioning

confidence: 99%

“…The neuron-intrinsic growth ability of CST neurons can be enhanced by deleting growth-inhibitory genes (18,19) or forcing the expression of pro-regenerative factors (20,21). A transcription factor called KLF6 has emerged as a particularly potent promoter of CST axon growth by activating a set of complementary gene networks involved in axon extension (22). Yet these neuron-intrinsic interventions only partially restore growth ability, and stimulated axons generally circumvent partial injuries, but fail to traverse complete injuries, suggesting persistent environmental inhibition (23).…”

Section: Introductionmentioning

confidence: 99%

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Restoration of Direct Corticospinal Communication Across Sites of Spinal Injury

Jayaprakash

Nowak

Eastwood

et al. 2019

Preprint

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Injury to the spinal cord often disrupts long-distance axon tracts that link the brain and spinal cord, causing permanent disability. Axon regeneration is then prevented by a combination of inhibitory signals that emerge at the injury site and by a low capacity for regeneration within injured neurons. The corticospinal tract (CST) is essential for fine motor control but has proven refractory to many attempted pro-regenerative treatments. Although strategies are emerging to create relay or detour circuits that reroute cortical motor commands through spared circuits, these have only partially met the challenge of restoring motor control. Here, using a murine model of spinal injury, we elevated the intrinsic regenerative ability of CST neurons by supplying a pro-regenerative transcription factor, KLF6, while simultaneously supplying injured CST axons with a growth-permissive graft of neural progenitor cells (NPCs) transplanted into a site of spinal injury. The combined treatment produced robust CST regeneration directly through the grafts and into distal spinal cord. Moreover, selective optogenetic stimulation of regenerated CST axons and single-unit electrophysiology revealed extensive synaptic integration by CST axons with spinal neurons beyond the injury site. Finally, when KLF6 was delivered to injured neurons with a highly effective retrograde vector, combined KLF6/NPC treatment yielded significant improvements in forelimb function. These findings highlight the utility of retrograde gene therapy as a strategy to treat CNS injury and establish conditions that restore functional CST communication across a site of spinal injury. Significance StatementDamage to the spinal cord results in incurable paralysis because axons that carry descending motor commands are unable to regenerate. Here we deployed a two-pronged strategy in a rodent model of spinal injury to promote regeneration by the corticospinal tract, a critical mediator of fine motor control. Delivering pro-regenerative KLF6 to injured neurons while simultaneously transplanting neural progenitor cells to injury sites resulted in robust regeneration directly through sites of spinal injury, accompanied by extensive synapse formation with spinal neurons. In addition, when KLF6 was delivered with improved retrograde gene therapy vectors, the combined treatment significantly improved forelimb function in injured animals. This work represents important progress toward restoring regeneration and motor function after spinal injury.

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“…2A,B). In contrast to prior findings (22), KLF6treated animals displayed only a non-significant trend toward enhanced CST growth in this injury paradigm (Supp. Fig.…”

Section: Resultscontrasting

confidence: 99%

Section: Resultssupporting

confidence: 65%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Restoration of Direct Corticospinal Communication Across Sites of Spinal Injury

Jayaprakash

Nowak

Eastwood

et al. 2019

Preprint

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Developmental Chromatin Restriction of Pro‐Growth Gene Networks Acts as an Epigenetic Barrier to Axon Regeneration in Cortical Neurons

Venkatesh

Mehra

Wang

et al. 2018

Developmental Neurobiology

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Axon regeneration in the central nervous system is prevented in part by a developmental decline in the intrinsic regenerative ability of maturing neurons. This loss of axon growth ability likely reflects widespread changes in gene expression, but the mechanisms that drive this shift remain unclear. Chromatin accessibility has emerged as a key regulatory mechanism in other cellular contexts, raising the possibility that chromatin structure may contribute to the age-dependent loss of regenerative potential. Here we establish an integrated bioinformatic pipeline that combines analysis of developmentally dynamic gene networks with transcription factor regulation and genome-wide maps of chromatin accessibility. When applied to the developing cortex, this pipeline detected overall closure of chromatin in sub-networks of genes associated with axon growth. We next analyzed mature CNS neurons that were supplied with various pro-regenerative transcription factors. Unlike prior results with SOX11 and KLF7, here we found that neither JUN nor an activated form of STAT3 promoted substantial corticospinal tract regeneration. Correspondingly, chromatin accessibility in JUN or STAT3 target genes was substantially lower than in predicted targets of SOX11 and KLF7. Finally, we used the pipeline to predict pioneer factors that could potentially relieve chromatin constraints at growth-associated loci. Overall this integrated analysis substantiates the hypothesis that dynamic chromatin accessibility contributes to the developmental decline in axon growth ability and influences the efficacy of pro-regenerative interventions in the adult, while also pointing toward selected pioneer factors as high-priority candidates for future combinatorial experiments. © 2018 Wiley Periodicals, Inc. Develop Neurobiol 00: 000-000, 2018.

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Silencing lncRNA HOTAIR improves the recovery of neurological function in ischemic stroke via the miR-148a-3p/KLF6 axis

Huang

Wang

Liu

et al. 2021

Brain Research Bulletin

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Ischemic stroke (IS), caused by a permanent or transient local reduction in blood supply to the brain, is one of the most widespread causes of public health problems in modern society. Long non-coding RNA (LncRNA) has been reported to be related to angiogenesis following IS. In this study, we explored the effect and potential molecular mechanism of lncRNA HOTAIR in IS. Permanent middle cerebral artery occlusion (pMCAO) model and oxygen and glucose deprivation (OGD) model were established. HOTAIR was increased in vivo and in vitro models post-ischemic. HOTAIR knockdown promoted neurological function recovery, manifesting in decreased modi ed neurological severity score, cerebral infarcted area, apoptosis and in ammation, and improved balance ability, spatial learning and memory ability. Silencing HOTAIR also improved the viability of OGD-induced N2a cells, and attenuated apoptosis and in ammation. HOTAIR can compete with KLF6 to bind to miR-148a-3p. miR-148a-3p knockdown or KLF6 overexpression partially reversed the effect of sh-HOTAIR on OGD-induced N2a cells. HOTAIR suppressed the activation of STAT3 pathway via the miR-148a-3p/KLF6 axis. To summarize, this study demonstrated that lncRNA HOTAIR absorbed miR-148a-3p and up-regulate KLF6 expression through ceRNA mechanism, and inhibited STAT3 pathway, promoted apoptosis and in ammation, and aggravated neurological injury post-IS.

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KLF6 and STAT3 co-occupy regulatory DNA and functionally synergize to promote axon growth in CNS neurons

Cited by 41 publications

References 77 publications

Restoration of Direct Corticospinal Communication Across Sites of Spinal Injury

Restoration of Direct Corticospinal Communication Across Sites of Spinal Injury

Developmental Chromatin Restriction of Pro‐Growth Gene Networks Acts as an Epigenetic Barrier to Axon Regeneration in Cortical Neurons

Silencing lncRNA HOTAIR improves the recovery of neurological function in ischemic stroke via the miR-148a-3p/KLF6 axis

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