Our research focuses on the molecular and cellular mechanisms of axon regeneration and neuronal differentiation for the repair of central nervous system (CNS) damage, with particular emphasis on Spinal Cord Injury (SCI) and Stroke.
Models employed include SCI, optic nerve crush and Stroke.
Spontaneous regeneration following injury in the CNS, including brain and spinal cord is extremely poor, whereas limited axon sprouting does occur, failure in effective axon regeneration and functional reinnervation do not allow significant behavioral recovery. The main reason being:
1. The presence of poor intrinsic neuronal capacity to regenerate axons
2. The presence of an inhibitory environment
3. Cell loss
In large part, functional recovery reflects the number of surviving cells and fiber tracts, the extent of neural plasticity, and the presence of a permissive environment for regeneration. Such processes are substantially regulated by gene expression changes; temporally, these alterations include an earlier phase associated with inflammation, axonal damage, cell death and loss, and a later one characterized by tentative axonal regeneration and the formation of an inhibitory environment and of the tissue scar.
Therefore, major aims of regenerative neuroscience are:
1. overcome the inhibitors of axonal regeneration and limiting the scar formation
2. enhance neuronal intrinsic axonal regeneration
3. protect and replace the original cellular environment
Aims and Approach
In vitro we employ both cell lines and primary neurons to study mechanisms of neurite outgrowth/axon regeneration and neuronal differentiation.
In vivo, we use models of Spinal Cord Injury, Stroke and Optic Nerve Crush in mice, including the use of transgenic animals to evaluate the in vivo effects of the modulation of specific molecular pathways upon regeneration and recovery of function.
More specifically, our lab focuses on how transcription can affect cytoskeleton remodeling in neurite/axon outgrowth, neuronal differentiation and axonal regeneration.
Transcription factors of interests include p53 and NFAT. We also investigate the role of DNA and histone modifying enzymes that affect the status of the transcriptional environment in neurons.
The role of the tumor suppressor p53 in axon outgrowth and regeneration
We have recently shown that the transcription factor p53 is required for neurite/axon growth following growth factor administration in vitro and is required for physiological nerve regeneration following axotomy in vivo (Di Giovanni et al., EMBO J, 2006; Tedeschi et al., CDD, 2009). Moreover, specifically acetylated p53 preferentially exerts these effects by triggering the expression of genes involved in cytoskeleton remodeling, which promote neurite and axon outgrowth. They include the actin binding protein Coronin 1b and the GTPase Rab13, which we have recently characterized. Nevertheless, the overall pro-axon growth effects of p53 cannot be accounted for by these two proteins. Recent data in the lab have shown that p53 signaling is relevant for the activation of important pro-axon outgrowth proteins such as GAP-43 or cGKI (Tedeschi et al., CDD, 2009, and J Neurosci, 2009). This project aims at defining the role for p53 in promoting axonal regeneration following spinal injuries and optic nerve crush and at investigating novel patterns of p53 signaling and new downstream p53 targets that are important for axon growth and regeneration following spinal and brain injuries
Retinoic acid and acetyl transferases-dependent pathways in neuronal outgrowth and axon regeneration
Acetylation increases gene expression and protect neurons from cell death. We have recently shown that acetylation of specific transcription factors including p53 can promote axon outgrowth on inhibitory substrates through specific histone modifying enzymes dependent pathways, including CBP/p300 and P/CAF (Gaub et al., CDD, in press). The goal of this project is to define the importance of acetylation and acetyltransferases mediated signalling in axon growth and regeneration on both permissive and inhibitory substrates (myelin) in vitro and in vivo. Currently the effects of retinoic acid and acetylation pathways on axon regeneration are under investigation in SCI and ONC in vivo models of axonal injury
Chromatin status and axon regeneration
Chromatin status profoundly affects transcription. DNA methylation and histone post-translational modifications are largely responsible to determine favorable chromatin conditions for specific occupancy of promoters by transcription factors and for transcription to work properly. Efficient and specific transcription is required for axon outgrowth and may play a role to promote axonal regeneration. We study the role of histone modifications and DNA methylation including how p53 may influence them, in in vivo models of axonal injury and regeneration taking advantage of the dorsal root ganglia system, at the cross road between the peripheral and the central nervous system
Transcriptional regulation in neuronal outgrowth and differentiation
Transcriptional control is essential to regulate neuronal outgrowth differentiation. Clarification of the molecular mechanisms of neural differentiation and outgrowth can help understanding some pro-regenerative molecular changes in the adult injured neurons that partially recapitulate development. Last, but not least, fostering neural differentiation could be useful to promote functional recovery following a variety of neurological disorders characterized by neuronal loss and damage. The roles of P53 and NFAT neuronal differentiation and outgrowth are currently been investigated in both physiological conditions and after experimental stroke
The role of the transcription factor SRF in axon regeneration
SRF is important for neurite and axonal outgrowth during development. In collaboration with Dr. Knöll at Ulm University, we are investigating the role of SRF molecular pathways in axon regeneration and during brain development
Ongoing collaborations include several colleagues:
Xiaochun Xu lab, Anderson Cancer Center, Houston, Texas, USA: http://gsbs.uth.tmc.edu/tutorial/xu_x.html
Prof. Dr. Hans Werner Müller, University of Düsseldorf, Germany, www.neurosciences-duesseldorf.de/principal-investigators-and-junior-researchers/hans-werner-mueller.html
PD Dr. Peter Heiduschka, University of Munster, Germany
Prof. Dr. Bernd Knöll, Institute for Physicological Chemistry, University of Ulm, Germany, www.uni-ulm.de/en/med/institute-of-physiological-chemistry/knoell.html
Prof. Dr. Frank Bradke, DZNE Bonn, Germany, www.dzne.de/en/sites/bonn/research-groups/bradke.html
Dr. Anne-Laurence Boutillier, Laboratoire de Neurosciences Cognitives et Adaptatives- Strasbourg, France, www.lnca.fr/20.html
Dr. Mike Fainzilber, Wiezmann Institute of Science-Rehovot, Israel, www.weizmann.ac.il/Biological_Chemistry/scientist/Fainzilber/Fainzilber.html
Dr. Michele Studer, TIGEM, Naples, Italy, studer(at)tigem.it
PD Dr. Andrea Wizenmann, Anatomy, University of Tuebingen, www.anatomie.uni-tuebingen.de/experimentell/mitarbeiter/wizenmann.html
Prof. Dr. Robert Feil, Interfaculty Institute for Biochemistry, University of Tuebingen, Germany robert.feil(at)uni-tuebingen.de
Please contact us if you are interested in collaborations:
Publikationen der letzten 5 Jahre
1. The MDM4/MDM2-p53-IGF1 axis controls axonal regeneration, sprouting and functional recovery after CNS injury. Yashashree Joshi*, Marilia Grando Soria*, Giorgia Quadrato, Gizem Inak, Luming Zhou, Arnau Hervera, Khizr Rathore, Mohamed Elnaggar, Cucchiarini Magali, Jeanne Christophe Marine, Radhika Puttagunta and Simone Di Giovanni. Brain 2015, in press.
2. DNA methylation temporal profiling following peripheral versus central nervous system axotomy. Ricco Lindner, Radhika Puttagunta, Tuan Nguyen & Simone Di Giovanni. Sci. Data 1:140038 doi: 10.1038/sdata.2014.38 (2014).
3. Modulation of GABAA Receptor Signaling Increases Neurogenesis and Suppresses Anxiety through NFATc4. Quadrato G, Elnaggar MY, Duman C, Sabino A, Forsberg K, Di Giovanni S. J Neurosci. 2014 Jun 18;34(25):8630-45. doi: 10.1523/JNEUROSCI.0047-14.2014.
4. PCAF-dependent epigenetic changes promote axonal regeneration in the central nervous system. Puttagunta R, Tedeschi A, Sória MG, Hervera A, Lindner R, Rathore KI, Gaub P, Joshi Y, Nguyen T, Schmandke A, Laskowski CJ, Boutillier AL, Bradke F, Di Giovanni S. Nat Commun. 2014 Apr 1;5:3527. doi: 10.1038/ncomms4527.
5. Adult neurogenesis in brain repair: cellular plasticity vs. cellular replacement. Quadrato G, Elnaggar MY, Di Giovanni S. Front Neurosci. 2014 Feb 12;8:17. doi:10.3389/fnins.2014.00017. eCollection 2014. No abstract available.
6. Cross Talk between Cellular Redox Status, Metabolism, and p53 in Neural Stem Cell Biology. Forsberg K, Di Giovanni S. Neuroscientist. 2014 Jan 31;20(4):326-342. [Epub ahead of print] Review.
7. The transcription factor serum response factor stimulates axon regeneration through cytoplasmic localization and cofilin interaction. Stern S, Haverkamp S, Sinske D, Tedeschi A, Naumann U, Di Giovanni S, Kochanek S, Nordheim A, Knöll B. J Neurosci. 2013 Nov 27;33(48):18836-48. doi: 10.1523/JNEUROSCI.3029-13.2013.
8. The tumor suppressor p53 fine-tunes reactive oxygen species levels and neurogenesis via PI3 kinase signaling. Forsberg K, Wuttke A, Quadrato G, Chumakov PM, Wizenmann A, Di Giovanni S. J Neurosci. 2013 Sep 4;33(36):14318-30. doi: 10.1523/JNEUROSCI.1056-13.2013.
9. Epigenetic regulation of axon outgrowth and regeneration in CNS injury: the first steps forward. Lindner R, Puttagunta R, Di Giovanni S. Neurotherapeutics. 2013 Oct;10(4):771-81. doi: 10.1007/s13311-013-0203-8. Review.
10. Cell-based therapy for the deficient urinary sphincter. Hart ML, Neumayer KM, Vaegler M, Daum L, Amend B, Sievert KD, Di Giovanni S, Kraushaar U, Guenther E, Stenzl A, Aicher WK. Curr Urol Rep. 2013 Oct;14(5):476-87. doi: 10.1007/s11934-013-0352-7. Review.
11. Gatekeeper between quiescence and differentiation: p53 in axonal outgrowth and neurogenesis. Quadrato G, Di Giovanni S. Int Rev Neurobiol. 2012;105:71-89. doi: 10.1016/B978-0-12-398309-1.00005-6. Review.
12. p53 Regulates the neuronal intrinsic and extrinsic responses affecting the recovery of motor function following spinal cord injury. Floriddia EM, Rathore KI, Tedeschi A, Quadrato G, Wuttke A, Lueckmann JM, Kigerl KA, Popovich PG, Di Giovanni S. J Neurosci. 2012 Oct 3;32(40):13956-70. doi: 10.1523/JNEUROSCI.1925-12.2012.
13. Serum Response Factor (SRF)-cofilin-actin signaling axis modulates mitochondrial dynamics. Beck H, Flynn K, Lindenberg KS, Schwarz H, Bradke F, Di Giovanni S, Knöll B. Proc Natl Acad Sci U S A. 2012 Sep 18;109(38):E2523-32. Epub 2012 Aug 27.
14. Waking up the sleepers: shared transcriptional pathways in axonal regeneration and neurogenesis. Quadrato G, Di Giovanni S. Cell Mol Life Sci. 2013 Mar;70(6):993-1007. doi: 10.1007/s00018-012-1099-x. Epub 2012 Aug 17. Review.
15. Neural regeneration: lessons from regenerating and non-regenerating systems. Ferreira LM, Floriddia EM, Quadrato G, Di Giovanni S. Mol Neurobiol. 2012 Oct;46(2):227-41. doi: 10.1007/s12035-012-8290-9. Epub 2012 Jun 21. Review.
16. Nuclear factor of activated T cells (NFATc4) is required for BDNF-dependent survival of adult-born neurons and spatial memory formation in the hippocampus. Quadrato G, Benevento M, Alber S, Jacob C, Floriddia EM, Nguyen T, Elnaggar MY, Pedroarena CM, Molkentin JD, Di Giovanni S. Proc Natl Acad Sci U S A. 2012 Jun 5;109(23):E1499-508. doi: 10.1073/pnas.1202068109. Epub 2012 May 14.
17. Retinoic acid signaling in axonal regeneration. Puttagunta R, Di Giovanni S. Front Mol Neurosci. 2012 Jan 3;4:59. doi: 10.3389/fnmol.2011.00059. eCollection 2011.
18. p53-Dependent pathways in neurite outgrowth and axonal regeneration. Di Giovanni S, Rathore K. Cell Tissue Res. 2012 Jul;349(1):87-95. doi: 10.1007/s00441-011-1292-5. Epub 2012 Jan 22. Review.
19. Chromatin immunoprecipitation from dorsal root ganglia tissue following axonal injury. Floriddia E, Nguyen T, Di Giovanni S. J Vis Exp. 2011 Jul 20;(53). pii: 2803. doi: 10.3791/2803.
20. The histone acetyltransferase p300 promotes intrinsic axonal regeneration. Gaub P, Joshi Y, Wuttke A, Naumann U, Schnichels S, Heiduschka P, Di Giovanni S. Brain. 2011 Jul;134(Pt 7):2134-48. doi: 10.1093/brain/awr142.
21. RA-RAR-β counteracts myelin-dependent inhibition of neurite outgrowth via Lingo-1 repression. Puttagunta R, Schmandke A, Floriddia E, Gaub P, Fomin N, Ghyselinck NB, Di Giovanni S. J Cell Biol. 2011 Jun 27;193(7):1147-56. doi: 10.1083/jcb.201102066. Epub 2011 Jun 20.
22. HDAC inhibition promotes neuronal outgrowth and counteracts growth cone collapse through CBP/p300 and P/CAF-dependent p53 acetylation. Gaub P, Tedeschi A, Puttagunta R, Nguyen T, Schmandke A, Di Giovanni S. Cell Death Differ. 2010 Sep;17(9):1392-408. doi: 10.1038/cdd.2009.216. Epub 2010 Jan 22.
23. The tumor suppressor p53 transcriptionally regulates cGKI expression during neuronal maturation and is required for cGMP-dependent growth cone collapse. Tedeschi A, Nguyen T, Steele SU, Feil S, Naumann U, Feil R, Di Giovanni S. J Neurosci. 2009 Dec 2;29(48):15155-60. doi: 10.1523/JNEUROSCI.4416-09.2009.
24. Molecular targets for axon regeneration: focus on the intrinsic pathways. Di Giovanni S. Expert Opin Ther Targets. 2009 Dec;13(12):1387-98. doi: 10.1517/14728220903307517. Review.
25. Valproic acid-mediated neuroprotection and regeneration in injured retinal ganglion cells. Biermann J, Grieshaber P, Goebel U, Martin G, Thanos S, Di Giovanni S, Lagrèze WA. Invest Ophthalmol Vis Sci. 2010 Jan;51(1):526-34. doi: 10.1167/iovs.09-3903. Epub 2009 Jul 23.
Zentrum für Neurologie
Hertie-Institut für klinische Hirnforschung
Abteilung Zellbiologie Neurologischer Erkrankungen
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