56 results found
Hervera A, De Virgiliis F, Palmisano I, et al., 2018, Reactive oxygen species regulate axonal regeneration through the release of exosomal NADPH oxidase 2 complexes into injured axons (vol 20, pg 307, 2018), NATURE CELL BIOLOGY, Vol: 20, Pages: 1098-1098, ISSN: 1465-7392
Palmisano I, Di Giovanni S, 2018, Advances and Limitations of Current Epigenetic Studies Investigating Mammalian Axonal Regeneration, NEUROTHERAPEUTICS, Vol: 15, Pages: 529-540, ISSN: 1933-7213
Hervera A, De Virgiliis F, Palmisano I, et al., 2018, Reactive oxygen species regulate axonal regeneration through the release of exosomal NADPH oxidase 2 complexes into injured axons, NATURE CELL BIOLOGY, Vol: 20, Pages: 307-+, ISSN: 1465-7392
Gonzalez-Billault C, Wilson C, Munoz E, et al., 2017, Novel mechanisms involving redox biology are essential to support axonal growth, ISN-ESN Meeting, Publisher: WILEY, Pages: 195-195, ISSN: 0022-3042
Wilson C, Munoz-Palma E, Henriquez DR, et al., 2016, A Feed-Forward Mechanism Involving the NOX Complex and RyR-Mediated Ca2+ Release During Axonal Specification, JOURNAL OF NEUROSCIENCE, Vol: 36, Pages: 11107-11119, ISSN: 0270-6474
Joshi Y, Soria MG, Quadrato G, et al., 2015, The MDM4/MDM2-p53-IGF1 axis controls axonal regeneration, sprouting and functional recovery after CNS injury, Brain, Vol: 138, Pages: 1843-1862, ISSN: 0006-8950
Regeneration of injured central nervous system axons is highly restricted, causing neurological impairment. To date, although the lack of intrinsic regenerative potential is well described, a key regulatory molecular mechanism for the enhancement of both axonal regrowth and functional recovery after central nervous system injury remains elusive. While ubiquitin ligases coordinate neuronal morphogenesis and connectivity during development as well as after axonal injury, their role specifically in axonal regeneration is unknown. Following a bioinformatics network analysis combining ubiquitin ligases with previously defined axonal regenerative proteins, we found a triad composed of the ubiquitin ligases MDM4, MDM2 and the transcription factor p53 (encoded by TP53) as a putative central signalling complex restricting the regeneration program. Indeed, conditional deletion of MDM4 or pharmacological inhibition of MDM2/p53 interaction in the eye and spinal cord promote axonal regeneration and sprouting of the optic nerve after crush and of supraspinal tracts after spinal cord injury. The double conditional deletion of MDM4-p53 as well as MDM2 inhibition in p53-deficient mice blocks this regenerative phenotype, showing its dependence upon p53. Genome-wide gene expression analysis from ex vivo fluorescence-activated cell sorting in MDM4-deficient retinal ganglion cells identifies the downstream target IGF1R, whose activity and expression was found to be required for the regeneration elicited by MDM4 deletion. Importantly, we demonstrate that pharmacological enhancement of the MDM2/p53-IGF1R axis enhances axonal sprouting as well as functional recovery after spinal cord injury. Thus, our results show MDM4-MDM2/p53-IGF1R as an original regulatory mechanism for CNS regeneration and offer novel targets to enhance neurological recovery.
Forsberg K, Di Giovanni S, 2014, Cross Talk between Cellular Redox Status, Metabolism, and p53 in Neural Stem Cell Biology, NEUROSCIENTIST, Vol: 20, Pages: 326-342, ISSN: 1073-8584
Quadrato G, Elnaggar MY, Duman C, et al., 2014, Modulation of GABAA Receptor Signaling Increases Neurogenesis and Suppresses Anxiety through NFATc4, JOURNAL OF NEUROSCIENCE, Vol: 34, Pages: 8630-8645, ISSN: 0270-6474
Puttagunta R, Tedeschi A, Soria MG, et al., 2014, PCAF-dependent epigenetic changes promote axonal regeneration in the central nervous system, NATURE COMMUNICATIONS, Vol: 5, ISSN: 2041-1723
Quadrato G, Elnaggar MY, Di Giovanni S, 2014, Adult neurogenesis in brain repair: cellular plasticity vs. cellular replacement, FRONTIERS IN NEUROSCIENCE, Vol: 8, ISSN: 1662-453X
Lindner R, Puttagunta R, Tuan N, et al., 2014, DNA methylation temporal profiling following peripheral versus central nervous system axotomy, SCIENTIFIC DATA, Vol: 1, ISSN: 2052-4463
Stern S, Haverkamp S, Sinske D, et al., 2013, The Transcription Factor Serum Response Factor Stimulates Axon Regeneration through Cytoplasmic Localization and Cofilin Interaction., The Journal Of Neuroscience, Vol: 33, Pages: 18836-18848
Hart ML, Neumayer KMH, Vaegler M, et al., 2013, Cell-based therapy for the deficient urinary sphincter., Curr Urol Rep, Vol: 14, Pages: 476-487
When sterile culture techniques of mammalian cells first became state of the art, there was tremendous anticipation that such cells could be eventually applied for therapeutic purposes. The discovery of adult human stem or progenitor cells further motivated scientists to pursue research in cell-based therapies. Although evidence from animal studies suggests that application of cells yields measurable benefits, in urology and many other disciplines, progenitor-cell-based therapies are not yet routinely clinically available. Stress urinary incontinence (SUI) is a condition affecting a large number of patients. The etiology of SUI includes, but is not limited to, degeneration of the urinary sphincter muscle tissue and loss of innervation, as well as anatomical and biomechanical causes. Therefore, different regimens were developed to treat SUI. However, at present, a curative functional treatment is not at hand. A progenitor-cell-based therapy that can tackle the etiology of incontinence, rather than the consequences, is a promising strategy. Therefore, several research teams have intensified their efforts to develop such a therapy for incontinence. Here, we introduce candidate stem and progenitor cells suitable for SUI treatment, show how the functional homogeneity and state of maturity of differentiated cells crucial for proper tissue integration can be assessed electrophysiologically prior to their clinical application, and discuss the trophic potential of adult mesenchymal stromal (or stem) cells in regeneration of neuronal function.
Lindner R, Puttagunta R, Di Giovanni S, 2013, Epigenetic regulation of axon outgrowth and regeneration in CNS injury: the first steps forward., Neurotherapeutics, Vol: 10, Pages: 771-781
Inadequate axonal sprouting and lack of regeneration limit functional recovery following neurologic injury, such as stroke, brain, and traumatic spinal cord injury. Recently, the enhancement of the neuronal regenerative program has led to promising improvements in axonal sprouting and regeneration in animal models of axonal injury. However, precise knowledge of the essential molecular determinants of this regenerative program remains elusive, thus limiting the choice of fully effective therapeutic strategies. Given that molecular regulation of axonal outgrowth and regeneration requires carefully orchestrated waves of gene expression, both temporally and spatially, epigenetic changes may be an ideal regulatory mechanism to address this unique need. While recent evidence suggests that epigenetic modifications could contribute to the regulation of axonal outgrowth and regeneration following axonal injury in models of stroke, and spinal cord and optic nerve injury, a number of unanswered questions remain. Such questions require systematic investigation of the epigenetic landscape between regenerative and non-regenerative conditions for the potential translation of this knowledge into regenerative strategies in human spinal and brain injury, as well as stroke.
Forsberg K, Wuttke A, Quadrato G, et al., 2013, The tumor suppressor p53 fine-tunes reactive oxygen species levels and neurogenesis via PI3 kinase signaling., J Neurosci, Vol: 33, Pages: 14318-14330
Mounting evidence points to a role for endogenous reactive oxygen species (ROS) in cell signaling, including in the control of cell proliferation, differentiation, and fate. However, the function of ROS and their molecular regulation in embryonic mouse neural progenitor cells (eNPCs) has not yet been clarified. Here, we describe that physiological ROS are required for appropriate timing of neurogenesis in the developing telencephalon in vivo and in cultured NPCs, and that the tumor suppressor p53 plays a key role in the regulation of ROS-dependent neurogenesis. p53 loss of function leads to elevated ROS and early neurogenesis, while restoration of p53 and antioxidant treatment partially reverse the phenotype associated with premature neurogenesis. Furthermore, we describe that the expression of a number of neurogenic and oxidative stress genes relies on p53 and that both p53 and ROS-dependent induction of neurogenesis depend on PI3 kinase/phospho-Akt signaling. Our results suggest that p53 fine-tunes endogenous ROS levels to ensure the appropriate timing of neurogenesis in eNPCs. This may also have implications for the generation of tumors of neurodevelopmental origin.
Quadrato G, Di Giovanni S, 2013, Waking up the sleepers: shared transcriptional pathways in axonal regeneration and neurogenesis., Cell Mol Life Sci, Vol: 70, Pages: 993-1007
In the last several years, relevant progress has been made in our understanding of the transcriptional machinery regulating CNS repair after acute injury, such as following trauma or stroke. In order to survive and functionally reconnect to the synaptic network, injured neurons activate an intrinsic rescue program aimed to increase their plasticity. Perhaps, in the attempt to switch back to a plastic and growth-competent state, post-mitotic neurons wake up and re-express a set of transcription factors that are also critical for the regulation of their younger brothers, the neural stem cells. Here, we review and discuss the transcriptional pathways regulating both axonal regeneration and neurogenesis highlighting the connection between the two. Clarification of their common molecular substrate may help simultaneous targeting of both neurogenesis and axonal regeneration with the hope to enhance functional recovery following CNS injury.
Floriddia EM, Rathore KI, Tedeschi A, et al., 2012, p53 Regulates the Neuronal Intrinsic and Extrinsic Responses Affecting the Recovery of Motor Function following Spinal Cord Injury, Journal of Neuroscience, Vol: 32, Pages: 13956-13970, ISSN: 0270-6474
Ferreira LMR, Floriddia EM, Quadrato G, et al., 2012, Neural regeneration: lessons from regenerating and non-regenerating systems., Mol Neurobiol, Vol: 46, Pages: 227-241
One only needs to see a salamander regrowing a lost limb to become fascinated by regeneration. However, the lack of robust axonal regeneration models for which good cellular and molecular tools exist has hampered progress in the field. Nevertheless, the nervous system has been revealed to be an excellent model to investigate regeneration. There are conspicuous differences in neuroregeneration capacity between amphibia and warm-blooded animals, as well as between the central and the peripheral nervous systems in mammals. Exploration of such discrepancies led to significant discoveries on the basic tenets of neuroregeneration in the last two decades, identifying several positive and negative regulators of axonal regeneration. Implications of these findings to the comprehension of mammalian regeneration and to the development of spinal cord injury therapies are also addressed.
Beck H, Flynn K, Lindenberg KS, et al., 2012, Serum Response Factor (SRF)-cofilin-actin signaling axis modulates mitochondrial dynamics, Proceedings of the National Academy of Sciences, Vol: 109, Pages: E2523-E2532, ISSN: 0027-8424
Di Giovanni S, Rathore K, 2012, p53-dependent pathways in neurite outgrowth and axonal regeneration, Cell and Tissue Research, Vol: 349, Pages: 87-95, ISSN: 0302-766X
Quadrato G, Benevento M, Alber S, et al., 2012, Nuclear factor of activated T cells (NFATc4) is required for BDNF-dependent survival of adult-born neurons and spatial memory formation in the hippocampus, Proceedings of the National Academy of Sciences, Vol: 109, Pages: E1499-E1508, ISSN: 0027-8424
Quadrato G, Di Giovanni S, 2012, Gatekeeper between quiescence and differentiation: p53 in axonal outgrowth and neurogenesis., Int Rev Neurobiol, Vol: 105, Pages: 71-89
The transcription factor and tumor suppressor gene p53 regulates a wide range of cellular processes including DNA damage/repair, cell cycle progression, apoptosis, and cell metabolism. In the past several years, a specific novel role for p53 in neuronal biology has emerged. p53 orchestrates the polarity of self-renewing divisions in neural stem cells both during embryonic development and in adulthood and coordinates the timing for cell fate specification. In postmitotic neurons, p53 regulates neurite outgrowth and postinjury axonal regeneration via neurotrophin-dependent and -independent signaling by both transcriptional and posttranslational control of growth cone remodeling. This review provides an insight into the molecular mechanisms upstream and downstream p53 both during neural development and following axonal injury. Their understanding may provide therapeutic targets to enhance neuroregeneration following nervous system injury.
Floriddia E, Nguyen T, Di Giovanni S, 2011, Chromatin immunoprecipitation from dorsal root ganglia tissue following axonal injury., J Vis Exp
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.
Gaub P, Joshi Y, Wuttke A, et al., 2011, The histone acetyltransferase p300 promotes intrinsic axonal regeneration, Brain, Vol: 134, Pages: 2134-2148, ISSN: 0006-8950
Puttagunta R, Schmandke A, Floriddia EM, et al., 2011, RA-RAR-β counteracts myelin-dependent inhibition of neurite outgrowth via Lingo-1 repression, Journal of Cell Biology, Vol: 193, Pages: 1147-1156, ISSN: 0021-9525
After an acute central nervous system injury, axonal regeneration is limited as the result of a lack of neuronal intrinsic competence and the presence of extrinsic inhibitory signals. The injury fragments the myelin neuronal insulating layer, releasing extrinsic inhibitory molecules to signal through the neuronal membrane- bound Nogo receptor (NgR) complex. In this paper, we show that a neuronal transcriptional pathway can interfere with extrinsic inhibitory myelin-dependent signaling, thereby promoting neurite outgrowth. Specifically, retinoic acid (RA), acting through the RA receptor β (RAR-β), inhibited myelin-activated NgR signaling through the transcriptional repression of the NgR complex member Lingo-1. We show that suppression of Lingo-1 was required for RA-RAR-β to counteract extrinsic inhibition of neurite outgrowth. Furthermore, we confirm in vivo that RA treatment after a dorsal column overhemisection injury inhibited Lingo-1 expression, specifically through RAR-β. Our findings identify a novel link between RA-RAR-β- dependent proaxonal outgrowth and inhibitory NgR complex-dependent signaling, potentially allowing for the development of molecular strategies to enhance axonal regeneration after a central nervous system injury. © 2011 Puttagunta et al.
Erharhaghen J, Bartz M, Di Giovanni S, et al., 2011, An unusual location of deep venous thrombosis associated with ischemic stroke and persistent foramen ovale., Case Rep Neurol, Vol: 3, Pages: 160-164
Up to 40% of ischemic strokes have no known cause (cryptogenic). The prevalence of persistent foramen ovale (PFO) amongst patients with cryptogenic stroke (CS) is twice as high as that of the normal population, therefore suggesting a causal relationship between the two entities. However, PFO by itself is not sufficient to cause stroke, as an embolic source is needed. This source is often unknown, making the causal relationship between CS and PFO hard to demonstrate. The most frequent, although still seldom, identifiable cause of embolism in an otherwise cryptogenic stroke associated with PFO is a deep venous thrombosis (DVT) of the lower extremities. Here, we present a unique case of brachiocephalic venous DVT associated with PFO and ischemic stroke in a young patient. As the search for DVT in patients with PFO and stroke is often limited to the lower extremities, this case may suggest that an unspecified number of DVTs are overlooked. Our report lends support to paradoxical embolism as a mechanism of stroke in patients with PFO and does, at least in selected cases, suggest a more detailed search for DVT beyond the lower extremities.
Puttagunta R, Di Giovanni S, 2011, Retinoic acid signaling in axonal regeneration., Front Mol Neurosci, Vol: 4
Following an acute central nervous system (CNS) injury, axonal regeneration and functional recovery are extremely limited. This is due to an extrinsic inhibitory growth environment and the lack of intrinsic growth competence. Retinoic acid (RA) signaling, essential in developmental dorsoventral patterning and specification of spinal motor neurons, has been shown through its receptor, the transcription factor RA receptor β2 (RARβ2), to induce axonal regeneration following spinal cord injury (SCI). Recently, it has been shown that in dorsal root ganglion neurons (DRGs), cAMP levels were greatly increased by lentiviral RARβ2 expression and contributed to neurite outgrowth. Moreover, RARβagonists, in cerebellar granule neurons (CGN) and in the brain in vivo, induced phosphoinositide 3-kinase dependent phosphorylation of AKT that was involved in RARβ-dependent neurite outgrowth. More recently, RA-RARβpathways were shown to directly transcriptionally repress a member of the inhibitory Nogo receptor (NgR) complex, Lingo-1, under an axonal growth inhibitory environment in vitro as well as following spinal injury in vivo. This perspective focuses on these newly discovered molecular mechanisms and future directions in the field.
Gaub P, Tedeschi A, Puttagunta R, et al., 2010, HDAC inhibition promotes neuronal outgrowth and counteracts growth cone collapse through CBP/p300 and P/CAF-dependent p53 acetylation., Cell Death Differ, Vol: 17, Pages: 1392-1408
Neuronal outgrowth is guided by both extrinsic and intrinsic factors, involving transcriptional regulation. The acetylation of histones and transcription factors, which facilitates promoter accessibility, ultimately promotes transcription, and depends on the balance between histone deacetylases (HDACs) and histone acetyltransferases (HATs) activities. However, a critical function for specific acetylation modifying enzymes in neuronal outgrowth has yet to be investigated. To address this issue, we have used an epigenetic approach to facilitate gene expression in neurons, by using specific HDAC inhibitors. Neurons treated with a combination of HDAC and transcription inhibitors display an acetylation and transcription-dependent increase in outgrowth and a reduction in growth cone collapse on both 'permissive' (poly-D-lysine, PDL) and 'non-permissive' substrates (myelin and chondroitin sulphate proteoglycans (CSPGs)). Next, we specifically show that the expression of the histone acetyltransferases CBP/p300 and P/CAF is repressed in neurons by inhibitory substrates, whereas it is triggered by HDAC inhibition on both permissive and inhibitory conditions. Gene silencing and gain of function experiments show that CBP/p300 and P/CAF are key players in neuronal outgrowth, acetylate histone H3 at K9-14 and the transcription factor p53, thereby initiating a pro-neuronal outgrowth transcriptional program. These findings contribute to the growing understanding of transcriptional regulation in neuronal outgrowth and may lay the molecular groundwork for the promotion of axonal regeneration after injury.
Biermann J, Grieshaber P, Goebel U, et al., 2010, Valproic acid-mediated neuroprotection and regeneration in injured retinal ganglion cells., Invest Ophthalmol Vis Sci, Vol: 51, Pages: 526-534
PURPOSE: Valproic acid (VPA) has been demonstrated to have neuroprotective effects in neurodegenerative conditions. VPA inhibits histone-deacetylases (HDAC) and delays apoptosis in degenerating neurons. The authors investigated whether VPA delays retinal ganglion cell (RGC) death and enhances axonal regeneration after optic nerve crush (ONC). Furthermore, potential molecular targets involved in VPA-mediated protection were analyzed. METHODS: ONC was performed on the left eye of rats, which received VPA or Ringer's solution subcutaneously (SC; 300 mg/kg twice daily) or intravitreally (single postlesional injection). Densities of fluorogold-labeled RGC were analyzed in retinal flatmounts after 5 or 8 days. Retinal tissue was also harvested and processed to quantify axon growth in retinal explants; evaluate caspase-3 activity; analyze transcription factor cAMP response element binding protein (CREB); and determine acetylated histone 3 and 4, as well as phosphorylated extracellular signal-regulated kinase (pERK) 1/2. RESULTS: Five and 8 days after ONC, 93% and 58% RGC survived after subcutaneous VPA treatment in comparison to Ringer's solution (62% and 37% viable RGC), respectively (P < 0.001). Likewise, a single intravitreal injection of VPA immediately after injury significantly delayed apoptosis in RGC (P = 0.0016). Injured RGC treated with VPA showed better regeneration of their axons in culture (196 axons/explant) than the crushed controls receiving Ringer (115 axons/explant). RGC axons of the right control eyes regenerated more after VPA treatment. VPA-mediated neuroprotection and neuroregeneration were accompanied by decreased caspase-3 activity, CREB induction, pERK1/2 activation, but not by altered histone-acetylation. CONCLUSIONS: VPA provided neuroprotection and axonal regrowth after ONC. Alterations were observed in several pathways; however, the precise mechanism of VPA-mediated protection is not yet fully understood.
Tedeschi A, Nguyen T, Steele SU, et al., 2009, The tumor suppressor p53 transcriptionally regulates cGKI expression during neuronal maturation and is required for cGMP-dependent growth cone collapse., J Neurosci, Vol: 29, Pages: 15155-15160
The cGMP-dependent protein kinase type I (cGKI) has multiple functions including a role in axonal growth and pathfinding of sensory neurons, and counteracts Semaphorin 3A (Sema3A)-induced growth cone collapse. Within the nervous system, however, the transcriptional regulation of cGKI is still obscure. Recently, the transcription factor and tumor suppressor p53 has been reported to promote neurite outgrowth by regulating the gene expression of factors that promote growth cone extension, but specific p53 targets genes that may counteract growth cone collapse have not been identified so far. Here, we show that p53 promotes cGKI expression in neuronal-like PC-12 cells and primary neurons by occupying specific regulatory elements in a chromatin environment during neuronal maturation. Importantly, we demonstrate that p53-dependent expression of cGKI is required for the ability of cGMP to counteract growth cone collapse. Growth cone retraction mediated by Sema3A is overcome by cGMP only in wild-type, but not in p53-null dorsal root ganglia. Reconstitution of p53 levels is sufficient to recover both cGKI expression and the ability of cGMP to counteract growth cone collapse, while cGKI overexpression rescues growth cone collapse in p53-null primary neurons. In conclusion, this study identifies p53 as a transcription factor that regulates the expression of cGKI during neuronal maturation and cGMP-dependent inhibition of growth cone collapse.
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