The role of cGMP-GKI signalling in spinal cord axonal sprouting and regeneration following injury
Final Report Abstract
In summary we found that cGMP-GKI signaling is essential for axonal regeneration of DRG sensory axons projecting into the dorsal columns after a SCI. However, cGMP-GKI axis is not important for axonal sprouting or regeneration of 5-HT raphespinal axons or CST and does not affect retraction or die-back of CST fibers, and it does not affect functional recovery after SCI. P53 that is upstream of cGMP-GKI, is required for functional recovery, axonal sprouting and regeneration of 5-HT raphespinal axons and limits CST retraction after SCI. However, the main mechanisms downstream these effects is IGF1 and not cGMP-cGKI. In fact IGF1 is required for p53 dependent enhancement of axonal sprouting and regeneration of 5-HT raphespinal and CST axons after SCI. Ultimately, these studies provided a novel understanding of p53-dependent pathways and of the role of cGMP-cGKI in the control of axonal sprouting and regeneration after SCI.
Publications
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P53 regulates the neuronal intrinsic and extrinsic responses affecting the recovery of motor function following spinal cord injury. J Neurosci. 2012 Oct 3;32(40):13956-70
Floriddia EM, Rathore KI, Tedeschi A, Quadrato G, Wuttke A, Lueckmann M, Kigerl KA, Popovich PG, Di Giovanni S
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The transcription factor serum response factor (SRF) stimulates axon regeneration through cytoplasmic localization and cofilin interaction. J Neurosci. 2013. Nov 27;33(48):18836-48
Stern S, Haverkamp S, Sinske D, Tedeschi T, Naumann U, Di Giovanni S, Kochanek S, Nordheim A, and Knöll, B
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The tumor suppressor p53 fine-tunes ROS levels and neurogenesis via PI3K signaling. J Neurosci. 2013 Sep 4;33(36):14318-30
Forsberg K, Wuttke A, Quadrato G, Chumakov PM, Wizenmann A, and Di Giovanni S
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DNA methylation temporal profiling following peripheral versus central nervous system axotomy. Scientific Data 11 Sept 2014
Lindner R, Puttagunta R, Nguyen T, Di Giovanni S
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PCAF-dependent epigenetic changes promote axonal regeneration in the central nervous system. Nature Comm. 2014 Apr 1;5:3527
Puttagunta R, Tedeschi A, Soria MG, Lindner R, Rahthore KI, Gaub P, Joshi Y, Nguyen T, Schmandke A, Bradke F, Di Giovanni S
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The MDM4/MDM2-p53-IGF1 axis controls axonal regeneration, sprouting and functional recovery after CNS injury. Brain. 2015 Jul;138(Pt 7):1843-62
Joshi Y, Soria M, Quadrato G, Inak G, Zhou Z, Hervera A, Rathore K, Elnagger M, Magali C, Marine JC, Puttagunta R, Di Giovanni S
