Molecular mechanisms of the suppression of axon regeneration by KLF transcription factors

Apara, Akintomide; Goldberg, Jeffrey L.

doi:10.4103/1673-5374.139454

Cited by 26 publications

(10 citation statements)

References 65 publications

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“…During early vertebrate eye development, a regulatory network of transcription factors regulates retinal cell differentiation ( Ohsawa and Kageyama, 2008 ) and survival into adulthood, including Pax6, Six3, Rx, Chx10, Notch, and Notch pathway components ( Badea and Nathans, 2011 ; Mu and Klein, 2004 ). KLFs including KLF4 regulate differentiation of other cell types throughout the body ( Apara and Goldberg, 2014 ; Moore et al, 2011 ), and KLF4 is one of a set of four factors capable of reprogramming somatic cells into induced pluripotent stem cells ( Hanna et al, 2008 ; Takahashi et al, 2007 ; Takahashi and Yamanaka, 2006 ; Welstead et al, 2008 ; Yu et al, 2007 ). KLF4 plays an important role in cell cycle arrest and growth inhibition ( Choi et al, 2006 ; Wei et al, 2005 , 2008 ), and is highly expressed in the postmitotic cells of both the gut and skin ( Shields et al, 1996 ; Zheng et al, 2009 ).…”

Section: Discussionmentioning

confidence: 99%

Krüppel-Like Factor 4 (KLF4) Is Not Required for Retinal Cell Differentiation

Fang

Shaw

Wang

et al. 2016

eNeuro

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During early vertebrate eye development, a regulatory network of transcription factors regulates retinal cell differentiation and survival into adulthood. Among those factors, Krüppel-like factor 4 (KLF4) plays the dual role of maintaining the stem cell status of retinal progenitors cells and repressing the intrinsic axon regeneration ability in retinal ganglion cells (RGCs) after injury. This study further investigated whether KLF4 plays a role in early retinal cell differentiation or survival into adulthood. We examined different types of retinal neurons, including RGCs, amacrine cells, bipolar cells, Müller cells, and photoreceptor cells, in adult mice in which KLF4 was conditionally deleted in early retinal development using Chx10-promoted Cre by immunohistochemistry. We compared the numbers of retinal neurons and the thickness of photoreceptor and nerve fiber layers between Chx10–Cre-driven KLF4 deletion mice and wild-type mice. There was no significant difference in cell number among any of the retinal cell types or in photoreceptor layer thickness with KLF4 deletion during early development. The thickness of axon bundles in the nerve fiber layer in the Chx10 conditional KLF4 knock-out mice was greater than that in wild-type mice. These results suggest that KLF4 is not required for retinal cell differentiation or survival, but does normally limit retinal ganglion cell axon bundle thickness. These data support a hypothesis that KLF4 suppresses axon growth during development.

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Section: Discussionmentioning

confidence: 99%

Krüppel-Like Factor 4 (KLF4) Is Not Required for Retinal Cell Differentiation

Fang

Shaw

Wang

et al. 2016

eNeuro

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“…The situation is much more challenging, however, for TFs such as SOX11 and KLFs. Although some information regarding KLF phosphorylation and acetylation is available, there remains a dearth of knowledge regarding upstream regulators of activity for these zinc finger factors [3, 57]. Thus for some factors, detection of TF-TF interactions via signaling cross-talk awaits more information regarding regulatory modifications and the development of PTM-specific antibodies.…”

Section: Cross-activation Through Downstream Effectorsmentioning

confidence: 99%

Selecting optimal combinations of transcription factors to promote axon regeneration: Why mechanisms matter

Venkatesh

Blackmore

2017

Neuroscience Letters

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Recovery from injuries to the central nervous system, including spinal cord injury, is constrained in part by the intrinsically low ability of many CNS neurons to mount an effective regenerative growth response. To improve outcomes, it is essential to understand and ultimately reverse these neuron-intrinsic constraints. Genetic manipulation of key transcription factors (TFs), which act to orchestrate production of multiple regeneration-associated genes, has emerged as a promising strategy. It is likely that no single TF will be sufficient to fully restore neuron-intrinsic growth potential, and that multiple, functionally interacting factors will be needed. An extensive literature, mostly from non-neural cell types, has identified potential mechanisms by which TFs can functionally synergize. Here we examine four potential mechanisms of TF/TF interaction; physical interaction, transcriptional cross-regulation, signaling-based cross regulation, and co-occupancy of regulatory DNA. For each mechanism, we consider how existing knowledge can be used to guide the discovery and effective use of TF combinations in the context of regenerative neuroscience. This mechanistic insight into TF interactions is needed to accelerate the design of effective TF-based interventions to relieve neuron-intrinsic constraints to regeneration and to foster recovery from CNS injury.

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“…JAK/STAT, PI3K/Akt and MAPK/ERK. 49,50 This can be achieved for example by deletion of Krüppel-like family of transcription factors (KLF), 51 osteopontin, 52 phosphatase and tensin homolog (PTEN) 44,53,54 and/or suppressor of cytokine signaling 3 solution (SOCS3), 53,54 activation of the mechanistic target of rapamycin (mTOR) signaling pathway, 52,55 administration of Rho kinase (ROCK) inhibitors, 56 overexpression of glycogen synthase kinase 3 (GSK3), 57 c-myc, 58 neuritin-1, 59 or thrombospondin.-1 60 From recent studies, it is clear that multiple strategies that focus on both extrinsic and intrinsic factors should be combined to maximize axon outgrowth. 37,38,44,[61][62][63][64] For example, intraocular inflammation, cAMP, and PTEN deletion were found to act synergistically to augment regeneration.…”

Section: The Retinofugal System As a Model To Study Axonal Regenerationmentioning

confidence: 99%

Neuroinflammation and Optic Nerve Regeneration: Where Do We Stand in Elucidating Underlying Cellular and Molecular Players?

Andries

Groef

Moons

2019

Current Eye Research

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Neurodegenerative diseases and central nervous system (CNS) trauma are highly irreversible, in part because adult mammals lack a robust regenerative capacity. A multifactorial problem underlies the limited axonal regeneration potential. Strikingly, neuroinflammation seems able to induce axonal regrowth in the adult mammalian CNS. It is increasingly clear that both blood-borne and resident inflammatory cells as well as reactivated glial cells affect axonal regeneration. The scope of this review is to give a comprehensive overview of the knowledge that links inflammation (with a focus on the innate immune system) to axonal regeneration and to critically reflect on the controversy that still prevails about the cells, molecules and pathways that are dominating the scene. Also, a brief overview is given of what is already known about the crosstalk between and the heterogeneity of cell types that might play a role in axonal regeneration. Recent research indicates that inflammation-induced axonal regrowth is not solely driven by a single-cell population but probably relies on the crosstalk between multiple cell types and the strong regulation of these cell populations in time and space. Moreover, there is growing evidence that the different cell populations are highly heterogeneous and as such can react differently upon injury. This could explain the controversial results that have been obtained over the past years. The primary focus of this manuscript is the retinofugal system of adult mammals, however, when relevant, insights or examples of the spontaneous regenerating zebrafish model and spinal cord research are added.

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Molecular mechanisms of the suppression of axon regeneration by KLF transcription factors

Cited by 26 publications

References 65 publications

Krüppel-Like Factor 4 (KLF4) Is Not Required for Retinal Cell Differentiation

Krüppel-Like Factor 4 (KLF4) Is Not Required for Retinal Cell Differentiation

Selecting optimal combinations of transcription factors to promote axon regeneration: Why mechanisms matter

Neuroinflammation and Optic Nerve Regeneration: Where Do We Stand in Elucidating Underlying Cellular and Molecular Players?

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