Intrinsic Axonal Growth and the Drive for Regeneration

O’Donovan, Kevin J.

doi:10.3389/fnins.2016.00486

Cited by 24 publications

(24 citation statements)

References 109 publications

(130 reference statements)

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“…Promoting effective regenerative axon growth after central nervous system (CNS) injury remains a critical unmet goal in neuroscience research. The success of axon regeneration depends on both the extrinsic availability of growth-permissive tissue substrate (Geoffroy and Zheng, 2014; Silver et al, 2015), as well as the cell-intrinsic capacity to produce and assemble the diverse set of cellular materials necessary for axon extension (Blackmore, 2012; He and Jin, 2016; O’Donovan, 2016; Tedeschi and Bradke, 2017). Transcription factors (TFs), which can orchestrate broad patterns of gene expression, have long been recognized as key determinants of the success of axon regeneration (Smith and Skene, 1997; Blackmore, 2012; Venkatesh and Blackmore, 2017).…”

Section: Introductionmentioning

confidence: 99%

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

Wang¹,

Mehra²,

Simpson³

et al. 2018

Preprint

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Members of the KLF family of transcription factors can exert both positive and negative effects on axon regeneration in the central nervous system, but the underlying mechanisms are unclear. KLF6 and −7 share nearly identical DNA binding domains and stand out as the only known growth-promoting family members. Here we confirm that similar to KLF7, expression of KLF6 declines during postnatal cortical development and that forced re-expression of KLF6 in corticospinal tract neurons of adult female mice enhances axon regeneration after cervical spinal injury. Unlike KLF7, however, these effects were achieved with wildtype KLF6, as opposed constitutively active mutants, thus simplifying the interpretation of mechanistic studies. To clarify the molecular basis of growth promotion, RNA sequencing identified 454 genes whose expression changed upon forced KLF6 expression in cortical neurons. Network analysis of these genes revealed sub-networks of downregulated genes that were highly enriched for synaptic functions, and sub-networks of upregulated genes with functions relevant to axon extension including cytoskeleton remodeling, lipid synthesis and transport, and bioenergetics. The promoter regions of KLF6-sensitive genes showed enrichment for the binding sequence of STAT3, a previously identified regeneration-associated gene. Notably, co-expression of constitutively active STAT3 along with KLF6 in cortical neurons produced synergistic increases in neurite length. Finally, genome-wide ATAC-seq footprinting detected frequent co-binding by the two factors in pro-growth gene networks, indicating co-occupancy as an underlying mechanism for the observed synergy. These findings advance understanding of KLF-stimulated axon growth and indicate functional synergy of KLF6 transcriptional effects with those of STAT3.SIGNIFICANCE STATEMENTThe failure of axon regeneration in the CNS limits recovery from damage and disease. These findings show the transcription factor KLF6 to be a potent promoter of axon growth after spinal injury, and more importantly clarify the underlying transcriptional changes. In addition, bioinformatics analysis predicted a functional interaction between KLF6 and a second transcription factor, STAT3, and genome-wide footprinting confirmed frequent co-occupancy. Co-expression of the two factors yielded synergistic elevation of neurite growth in primary neurons. These data point the way toward novel transcriptional interventions to promote CNS regeneration.

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Section: Introductionmentioning

confidence: 99%

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

Wang¹,

Mehra²,

Simpson³

et al. 2018

Preprint

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“…Along the years, diverse in vitro approaches have helped to reveal some of the pathways involved in axonal regrowth. Here, we summarize some of the most important findings regarding intrinsic capacity of RGC axon growth [for more detailed reviews (Crair and Mason, ; Fischer and Leibinger, ; Liu et al ., ; O'Donovan, )].…”

Section: Rgcs Regenerationmentioning

confidence: 99%

Cranial Pair II: The Optic Nerves

Herrera

Agudo‐Barriuso²,

Murcia‐Belmonte

2018

The Anatomical Record

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The optic nerves (ONs), one of the 12 pairs of cranial nerves (Pair II), together with the olfactory and the cochlear nerves, are devoted to transmit sensory inputs. In particular, ONs convey visual information from the retina to the brain. In mammals, the ONs are bilateral structures that extend from the optic disc to the optic chiasm containing glial cells and retinal ganglion cells (RGCs) axons. RGCs are the only retinal neurons able to collect visual information and transmit it to the visual centers in the brain for its processing and integration with the rest of sensory inputs. During embryonic development, RGCs born in the retina extend their axons to exit the eye and follow a stereotypic path outlined by the transient expression of a wide set of guidance molecules. As the rest of central nervous system structures, the ONs are covered with myelin produced by oligodendrocytes and wrapped by the meninges. ON injuries or RGCs degenerative conditions may provoke partial or complete blindness because they are incapable of spontaneous regeneration. Here, we first review major advances on the current knowledge about the mechanisms underlying the formation of the ONs in mammals. Then, we discuss some of the human disorders and pathologies affecting the development and function of the ONs and finally we comment on the existing view about ON regeneration possibilities. Anat Rec, 302:428-445, 2019.

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“…Recovery from injury to the central nervous system (CNS) is hampered by the inability of most axons to regenerate (Blackmore, 2012;Geoffroy et al, 2016;He and Jin, 2016). One reason for this failure is that many mammalian CNS neurons undergo a developmental decline in their intrinsic capacity for axon growth, reflecting both a sharp decrease in the expression of progrowth genes across age and a corresponding increase in the expression of growth inhibitory genes (Moore et al, 2009;Liu et al, 2011;Sun et al, 2011;Du et al, 2015;Simpson et al, 2015;He and Jin, 2016;O'Donovan, 2016). To guide ongoing efforts to reprogram adult neurons back to a regeneration-competent state, it is important to clarify the intrinsic cellular mechanisms that underlie these developmental shifts in gene expression.…”

Section: Introductionmentioning

confidence: 99%

Developmental chromatin restriction of pro-growth gene networks acts as an epigenetic barrier to axon regeneration in cortical neurons

Venkatesh¹,

Mehra²,

Wang³

et al. 2018

Preprint

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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 agedependent 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 growthassociated 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.peer-reviewed)

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Intrinsic Axonal Growth and the Drive for Regeneration

Cited by 24 publications

References 109 publications

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

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

Cranial Pair II: The Optic Nerves

Developmental chromatin restriction of pro-growth gene networks acts as an epigenetic barrier to axon regeneration in cortical neurons

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