CXCR4 in neurophysiology and neurodegeneration

Regeneration of the peripheral nervous system (PNS) relies on an orchestrated response involving not only motor neurons (MNs), but also other type of cells, and a plethora of mediators, with central and peripheral contributions. Axonal injury activates a transcriptional programming in neuronal cell bodies in the spinal cord that drives a polarized axon regrowth over long distances, to reconnect damaged axons with their original targets. This process is coordinated by different peripheral glial cells holding key roles in promoting re-innervation, which localize along the nerve - myelinating Schwann cells (mSCs) – or at the neuromuscular junction (NMJ) - perysinaptic Schwann cells (PSCs). Our research group has helped to identify the molecular components of the crosstalk driving neurotransmission recovery at the regenerating NMJ following an acute presynaptic injury. By exploiting the presynaptic neurotoxin α-LTx, which causes the reversible degeneration of the motor axon terminal (MAT) at the NMJ, the reviving of the developmental axis Cxcl12α-Cxcr4 and its role in the rescue of synaptic functionality were recently highlighted. Indeed, upon injury the receptor becomes re-expressed by the axonal stump, and its activation by the natural ligand, the chemokine Cxcl12α, as well as by the agonist NUCC-390, promotes a faster recovery of function of the NMJ. These findings suggest that Cxcr4 is potential pharmacological target to counteract nerve degeneration and promote neurotransmission rescue. Given the role of this molecular axis in peripheral nerve repair, my PhD project aims at elucidating the dynamics of Cxcr4 in PNS physiology and upon injury. To achieve this goal, I investigated Cxcr4 transcription, expression and localization in time and space by employing in vivo models of acute nerve injuries, and by detecting Cxcr4 protein and transcript through immunostaining and RNAscope technology, respectively. I discovered that Cxcr4 re-expression following injury is driven by both central and peripheral mechanisms, which come into play at distinct temporal stages. The early expression of the receptor at the injury site upon a sciatic nerve damage, and even much more distally, 8 at the NMJ, together with the axonal localization of CXCR4 transcripts, speak in favor of a local translation of CXCR4 mRNA as an early response to nerve damage. Moreover, our preliminary results point to mSCs and the muscle as possible sources of CXCR4 transcripts for the axon and at the NMJs, respectively. Furthermore, I explored the impact of Cxcr4 agonists on axonal growth and cAMP levels - being cAMP a major signaling pathway downstream of Cxcr4 engagement - in search of the most effective activator of Cxcr4 in a therapeutic perspective.