Identification of candidate transcriptional modulators involved in successful regeneration after nerve injury

Stam, Floor J.; MacGillavry, Harold D.; Armstrong, Nicola J.; Gunst, Mathisca C. M. de; Zhang, Yi; Kesteren, Ronald E. van; Smit, August B.; Verhaagen, Joost

doi:10.1111/j.1460-9568.2007.05597.x

Cited by 119 publications

(131 citation statements)

References 64 publications

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“…This increase in regenerative potential of the neuron is accompanied by regulated changes in thousands of genes in the dorsal root ganglia [47,116]. Collectively, these changes in transcriptional programs represent a change in the intrinsic regenerative state of the neuron.…”

Section: Intrinsic Capacity To Regeneratementioning

confidence: 99%

Neurotrophins: Potential Therapeutic Tools for the Treatment of Spinal Cord Injury

Hollis

Tuszynski

2011

Neurotherapeutics

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Spinal cord injury permanently disrupts neuroanatomical circuitry and can result in severe functional deficits. These functional deficits, however, are not immutable and spontaneous recovery occurs in some patients. It is highly likely that this recovery is dependent upon spared tissue and the endogenous plasticity of the central nervous system. Neurotrophic factors are mediators of neuronal plasticity throughout development and into adulthood, affecting proliferation of neuronal precursors, neuronal survival, axonal growth, dendritic arborization and synapse formation. Neurotrophic factors are therefore excellent candidates for enhancing axonal plasticity and regeneration after spinal cord injury. Understanding growth factor effects on axonal growth and utilizing them to alter the intrinsic limitations on regenerative growth will provide potent tools for the development of translational therapeutic interventions for spinal cord injury.Keywords Neurotrophin . spinal cord injury . regeneration . axon plasticity . functional recovery Human Spinal Cord InjuryTraumatic injury of the spinal cord can produce a range of debilitating effects and permanently alter the capabilities and quality of life of its surviving victims. Damage to the central nervous system (CNS) in general results in destruction of neuronal circuitry. Contusion, compression, and penetration injuries of the spinal cord can interrupt the flow of sensory and motor information between the brain and periphery [1]. Depending on the location and severity of the injury, deficits can range from weakness of limb movement to total paralysis and ventilator-assisted respiration. Spontaneous functional recovery is limited, but can and often does occur in patients with initial sparing of sensorimotor function [2]. This recovery, which plateaus between 12 to 18 months, is very likely due to sparing and sprouting of axons within the zone of partial preservation, an area where some motor function remains intact, immediately adjacent to the lesion site [2].Approximately 40% of humans that sustain spinal cord injury (SCI) exhibit improvement from their early postinjury baseline, and this spontaneous recovery can range from modest to extensive [2]. Spontaneous recovery primarily appears to depend on the extent of tissue sparing at the injury site, allowing compensatory axonal sprouting and systems reorganization at levels ranging from the spinal cord to the cerebral cortex [3][4][5][6][7][8][9][10]. However, in cases of more severe injuries, means of enhancing endogenous levels of axonal sprouting and inducing true axonal regeneration are required to enhance functional outcomes.Electronic supplementary material The online version of this article

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Section: Intrinsic Capacity To Regeneratementioning

confidence: 99%

Neurotrophins: Potential Therapeutic Tools for the Treatment of Spinal Cord Injury

Hollis

Tuszynski

2011

Neurotherapeutics

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“…In addition, ankrd1 has also been identified as a candidate gene that can play an important role in congenital cardiac (Cinquetti et al, 2008) and skeletal muscle (Bakay et al, 2002;Nakada et al, 2003) disease, as well as in angiogenesis (Boengler et al, 2003), neovascularization (Shi et al, 2005;Samaras et al, 2007) and neurite outgrowth (Stam et al, 2007). In in vivo experimental settings, ANKRD1 is used as a surrogate biomarker of cardiac hypertrophy (Aihara et al, 2000), cardio-toxic damage (Torrado et al, 2004) or skeletal myopathy (Casey et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Intron retention generates ANKRD1 splice variants that are co-regulated with the main transcript in normal and failing myocardium

Torrado

Iglesias

Nespereira

et al. 2009

Gene

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The cardiac ankyrin repeat domain 1 protein (ANKRD1, also known as CARP) has been extensively characterized with regard to its proposed functions as a cardio-enriched transcriptional co-factor and stressinducible myofibrillar protein. The present results show the occurrence of alternative splicing by intron retention events in the pig and human ankrd1 gene. In pig heart, ankrd1 is expressed as four alternatively spliced transcripts, three of which have non-excised introns: ankrd1-contained introns 6, 7 and 8 (i.e., ankrd1-i6,7,8), ankrd1-contained introns 7 and 8 (i.e., ankrd1-i7,8), and ankrd1 retained only intron 8 (i.e., ankrd1-i8). In the human heart, two orthologues of porcine intron-retaining ankrd1 variants (i.e., ankrd1-i8 and ankrd1-i7,8) are detected. We demonstrate that these newly-identified intron-retaining ankrd1 transcripts are functionally intact, efficiently translated into protein in vitro and exported to the cytoplasm in cardiomyocytes in vivo. In the piglet heart, both the intronless and intron-retaining ankrd1 mRNAs are co-expressed in a chamber-dependent manner being more abundant in the left as compared to the right myocardium. Our data further indicate co-upregulation of the ankrd1 spliced variants in myocardium in the porcine model of diastolic heart failure. Most significantly, we demonstrate that in vivo forced expression of recombinant intronless ankrd1 markedly increases the levels of intron-retaining ankrd1 variants (but not of the endogenous main transcript) in piglet myocardium, suggesting that ANKRD1 may positively regulate the expression of its own intron-containing RNAs in response to cardiac stress. Overall, our findings demonstrate that in cardiomyocytes ANKRD1 can exist in multiple isoforms which may contribute to the functional diversity of this factor in heart development and disease. Abbreviations ANKRD1, ankyrin repeat domain 1 protein; MARPs, muscle ankyrin repeat proteins; SRF, serum response factor; HF, heart failure; DHF, diastolic HF; LV/RV, left/right ventricular myocardium; LA/RA, left/right atrial

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“…Among the up-regulated genes were a number that are also induced after sciatic nerve lesion (25) and have demonstrated roles in promoting axon regeneration in other systems (Dataset S3). These include small proline-rich repeat protein 1A (Sprr1a), fibroblast growth factor-inducible 14 (Fn14), and heat shock protein beta-1 (Hspb1) (26)(27)(28), as well as the transcription factors activating transcription factor 3 (ATF3) and Kruppel-like factor 6 (Klf6) (29,30).…”

Section: G K O and R)mentioning

confidence: 99%

DLK initiates a transcriptional program that couples apoptotic and regenerative responses to axonal injury

Watkins¹,

Wang²,

Huntwork‐Rodriguez³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

291

427

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The cell intrinsic factors that determine whether a neuron regenerates or undergoes apoptosis in response to axonal injury are not well defined. Here we show that the mixed-lineage dual leucine zipper kinase (DLK) is an essential upstream mediator of both of these divergent outcomes in the same cell type. Optic nerve crush injury leads to rapid elevation of DLK protein, first in the axons of retinal ganglion cells (RGCs) and then in their cell bodies. DLK is required for the majority of gene expression changes in RGCs initiated by injury, including induction of both proapoptotic and regeneration-associated genes. Deletion of DLK in retina results in robust and sustained protection of RGCs from degeneration after optic nerve injury. Despite this improved survival, the number of axons that regrow beyond the injury site is substantially reduced, even when the tumor suppressor phosphatase and tensin homolog (PTEN) is deleted to enhance intrinsic growth potential. These findings demonstrate that these seemingly contradictory responses to injury are mechanistically coupled through a DLK-based damage detection mechanism.A xonal damage results in significant neuronal cell death and axon degeneration, often leading to permanent functional deficits. For example, optic nerve crush rapidly induces a stress response in retinal ganglion cells (RGCs) that includes profound alterations in gene expression patterns (1) and ultimately leads to apoptosis of these neurons (2). As axon injury may occur a significant distance from the cell body, it has been proposed that retrograde molecular motors play a critical role in conveying damage signals to the nucleus, allowing the cell to respond to damage (3). Attenuation of this transport mechanism has been shown to reduce degeneration, suggesting that the ability of the nucleus to detect an insult is an essential component of the injury response (4).Recent data suggest that dual leucine zipper kinase (DLK) is an essential component of the neuronal response to axon damage. DLK protein is present in axons, and protein levels are increased in response to axonal injury (5). Loss of DLK has been shown to protect distal axons from Wallerian degeneration (6) and to abrogate stress-induced retrograde c-Jun N-terminal kinase (JNK) signaling through interaction with the scaffolding protein JNK-interacting protein 3 (JIP3) (7-9). In many instances, injury-induced JNK activation in neurons results in apoptosis through phosphorylation of activator protein 1 (AP-1) transcription factors such as c-Jun, which initiates a proapoptotic gene expression program (10, 11). Consistent with this, genetic deletion of JNK2 and/or JNK3 is sufficient to protect neurons from degeneration in a range of CNS injury models, including axotomy (12-14), although the role of DLK in these contexts is not known.In contrast, DLK has been shown to regulate axon regeneration after axonal injury in adult peripheral nerves (9) and invertebrate systems (5, 15). The mechanism underlying the divergence between these apoptotic and reg...

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Identification of candidate transcriptional modulators involved in successful regeneration after nerve injury

Cited by 119 publications

References 64 publications

Neurotrophins: Potential Therapeutic Tools for the Treatment of Spinal Cord Injury

Neurotrophins: Potential Therapeutic Tools for the Treatment of Spinal Cord Injury

Intron retention generates ANKRD1 splice variants that are co-regulated with the main transcript in normal and failing myocardium

DLK initiates a transcriptional program that couples apoptotic and regenerative responses to axonal injury

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