A p53-CBP/p300 transcription module is required for GAP-43 expression, axon outgrowth, and regeneration

Tedeschi, Andrea; Nguyen, Tuan; Puttagunta, Radhika; Gaub, Perrine; Giovanni, Simone Di

doi:10.1038/cdd.2008.175

Cited by 126 publications

(138 citation statements)

References 45 publications

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“…However, recent experimental evidence 32 and our own work using HDAC class I and HDAC class I and II inhibitors 33 has proven this to be insufficient in producing postlesion regeneration of sensory fibres following a spinal or optic nerve injury and therefore unlikely the key to unlocking the molecular mechanisms of regeneration. While our work here describes that specific epigenetic codes are induced endogenously following a conditioning lesion that leads to CNS regeneration, it is also consistent with previous findings from our laboratory that showed the presence of a transcriptional complex formed by p53, p300 and PCAF in the proximity of several RAGs including GAP-43, Coronin 1b and Rab13 in primary neurones as well as facial motor neurones in a PNS facial nerve axotomy model [34][35][36] . Additionally, we found that the histone acetyltransferase p300 (which may form a complex with PCAF) is developmentally regulated in retinal ganglion cells and whose overexpression drives axonal regeneration of the injured optic nerve 33 .…”

Section: Discussionsupporting

confidence: 77%

“…RNA was extracted using PeqGOLD TriFast reagent (peqlab), cDNA was synthesized from 1 mg of total RNA using both oligodT and random hexamers from the SuperScript II Reverse Transcriptase kit (Invitrogen) and a real time RT-PCR was performed using Absolute QPCR SYBR low ROX master mix (Thermo Scientific). Quantities and fold changes were calculated following the manufacturer's instructions (ABI 7,500) and as previously reported 35,43 . Primer sequences are shown in Supplementary Table 1.…”

Section: Methodsmentioning

confidence: 99%

“…Real-time Q-PCR was run using Absolute QPCR SYBR low ROX master mix (Thermo Scientific). Quantities and fold changes were calculated following the manufacturer's instructions (ABI 7,500) and as previously reported 35,43 . Primers were designed in proximity (within 500 bp upstream) of the TSS.…”

Section: Methodsmentioning

confidence: 99%

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PCAF-dependent epigenetic changes promote axonal regeneration in the central nervous system

et al. 2014

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Section: Discussionsupporting

confidence: 77%

Section: Methodsmentioning

confidence: 99%

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PCAF-dependent epigenetic changes promote axonal regeneration in the central nervous system

et al. 2014

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“…We have previously found that p53 can occupy the promoters and drive the expression of a number of genes involved in neurite and axonal outgrowth such as Coronin 1b, Rab13 (Di , and GAP-43 (Tedeschi et al, 2009a;Floriddia et al, 2011). Moreover, p53 transcriptionally enhances the expression of cGKI, thereby inhibiting semaphorin 3A-dependent growth cone collapse in primary cortical and dorsal root ganglia neurons (Tedeschi et al, 2009b).…”

Section: Discussionmentioning

confidence: 99%

p53 Regulates the Neuronal Intrinsic and Extrinsic Responses Affecting the Recovery of Motor Function following Spinal Cord Injury

et al. 2012

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Following spinal trauma, the limited physiological axonal sprouting that contributes to partial recovery of function is dependent upon the intrinsic properties of neurons as well as the inhibitory glial environment. The transcription factor p53 is involved in DNA repair, cell cycle, cell survival, and axonal outgrowth, suggesting p53 as key modifier of axonal and glial responses influencing functional recovery following spinal injury. Indeed, in a spinal cord dorsal hemisection injury model, we observed a significant impairment in locomotor recovery in p53 Ϫ/Ϫ versus wild-type mice. p53 Ϫ/Ϫ spinal cords showed an increased number of activated microglia/macrophages and a larger scar at the lesion site. Loss-and gain-of-function experiments suggested p53 as a direct regulator of microglia/macrophages proliferation. At the axonal level, p53 Ϫ/Ϫ mice showed a more pronounced dieback of the corticospinal tract (CST) and a decreased sprouting capacity of both CST and spinal serotoninergic fibers. In vivo expression of p53 in the sensorimotor cortex rescued and enhanced the sprouting potential of the CST in p53 Ϫ/Ϫ mice, while, similarly, p53 expression in p53 Ϫ/Ϫ cultured cortical neurons rescued a defect in neurite outgrowth, suggesting a direct role for p53 in regulating the intrinsic sprouting ability of CNS neurons. In conclusion, we show that p53 plays an important regulatory role at both extrinsic and intrinsic levels affecting the recovery of motor function following spinal cord injury. Therefore, we propose p53 as a novel potential multilevel therapeutic target for spinal cord injury.

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“…Epigenetic modification of histones and DNA at these sites can also be simultaneously monitored. A similar protocol can be performed following facial nerve lesion, where the facial nerve nuclei can be dissected from the brainstem and processed by ChIP as we previously reported (Tedeschi et al, 2009). …”

Section: Discussionmentioning

confidence: 99%

Chromatin Immunoprecipitation from Dorsal Root Ganglia Tissue following Axonal Injury

Floriddia

Nguyen

Giovanni

2011

JoVE

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Axons in the central nervous system (CNS) do not regenerate while those in the peripheral nervous system (PNS) do regenerate to a limited extent after injury (Teng et al., 2006). It is recognized that transcriptional programs essential for neurite and axonal outgrowth are reactivated upon injury in the PNS (Makwana et al., 2005). However the tools available to analyze neuronal gene regulation in vivo are limited and often challenging.The dorsal root ganglia (DRG) offer an excellent injury model system because both the CNS and PNS are innervated by a bifurcated axon originating from the same soma. The ganglia represent a discrete collection of cell bodies where all transcriptional events occur, and thus provide a clearly defined region of transcriptional activity that can be easily and reproducibly removed from the animal. Injury of nerve fibers in the PNS (e.g. sciatic nerve), where axonal regeneration does occur, should reveal a set of transcriptional programs that are distinct from those responding to a similar injury in the CNS, where regeneration does not take place (e.g. spinal cord). Sites for transcription factor binding, histone and DNA modification resulting from injury to either PNS or CNS can be characterized using chromatin immunoprecipitation (ChIP).Here, we describe a ChIP protocol using fixed mouse DRG tissue following axonal injury. This powerful combination provides a means for characterizing the pro-regeneration chromatin environment necessary for promoting axonal regeneration. Protocol Sciatic & dorsal column nerve injury NOTE:The same incision is made to expose the sciatic nerve, but the wound is sutured closed leaving the nerve intact for the sham injury. NOTE:For most experiments, the laminectomy is considered the Sham injury. The animal is placed on a surgical towel and underneath it a thermopad is present throughout the procedure keeping the body temperature of the mouse at 37°C. All animals are anesthetized for surgery with a continuous isoflurane/O2 administration. Surgical instruments are autoclaved before the procedure. 2. For sciatic injury, both hindquarters are carefully shaved, and depilation is completed with generic hair remover prior to cleansing skin with alcohol followed by Betadyne 3 times. 3. The sciatic nerve is exposed by making a 4 mm incision posterior and parallel to the femur at mid-thigh through the skin and by spreading the muscles apart of the biceps femoris with fine forceps. 4. The exposed sciatic nerve is then injured , and the skin is closed with two suture clips.5. For dorsal column injury, the back of the mouse is carefully shaved, and depilation is completed with generic hair remover prior to cleansing the skin with alcohol spray/swipe. 6. The spinal cord is exposed by making a 2.5 cm incision from about T7 to T13. The skin is spread apart, and the connective tissue is removed along the vertebra from T9 to T11. 7. A laminectomy is performed at T10 level 8. A few drops of Xylocain are added to the tissue to anaesthetize the cord, and the dura mater is...

show abstract

A p53-CBP/p300 transcription module is required for GAP-43 expression, axon outgrowth, and regeneration

Cited by 126 publications

References 45 publications

PCAF-dependent epigenetic changes promote axonal regeneration in the central nervous system

PCAF-dependent epigenetic changes promote axonal regeneration in the central nervous system

p53 Regulates the Neuronal Intrinsic and Extrinsic Responses Affecting the Recovery of Motor Function following Spinal Cord Injury

Chromatin Immunoprecipitation from Dorsal Root Ganglia Tissue following Axonal Injury

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