The role of cGMP-GKI signalling in spinal cord axonal sprouting and regeneration following injury

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Spinal cord injury leads to long term neurological impairment that largely depends upon the incapacity of lesioned spinal axons to sprout and regenerate and to re-establish appropriate synaptic contacts1-3. The limited or absent regenerative ability of injured axons is primarily due to the collapse of their growth cones. The cGMP-dependent protein kinase type I (cGKI) has multiple functions including a role in axonal growth and pathfinding of sensory neurons, and counteracts growth cone collapse induced by Semaphorin 3A (Sema3A), which also limits regeneration following spinal injuries4. We have recently shown that neuronal cGKI expression is directly regulated by the transcription factor p53, which is required for physiological axonal regeneration5,6. However, a role for cGMP-GKI pathways in p53 dependent and independent axonal outgrowth and regeneration following spinal injuries remains elusive. We hypothesize that cGMP-GKI cascade is essential for physiological axonal sprouting and for axonal regeneration and that cGMP-GKI gain of function experiments would lead to enhanced axonal sprouting and regeneration following spinal injury, including in mice lacking neuronal p53. We will employ a spinal dorsal overhemisection at T8 in mice to specifically investigate (1) axonal regeneration and sprouting as well as functional recovery in mice lacking cGKI in nestin positive neurons (cGKI nestin -/-) and (2) the capacity of enhanced cGMP-cGKI signaling (via pharmacological means and viral cGKI delivery) to promote axonal sprouting and regeneration in wild type as well as in p53 loxP/nestin cre mice.Ultimately, this study may provide novel molecular and pharmacological tools to enhance axonal regeneration following spinal lesions and may clarify the cGMP-cGKI as well as the p53-dependent pro-regeneration pathways.