Seite: Arbeitsgruppen > Neuroregeneration (Di Giovanni) > Research Directions
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