Our research group studies from several years the role played by the growth factor Neuregulin1 (NRG1) in the peripheral nerve regeneration (in close collaboration with the Human Anatomy Group) and in the migration of neuronal progenitors (in close collaboration with Neuroscience Institute Cavalieri Ottolenghi).
Different isoforms of NRG1 were described which derive by alternative splicing of exons, giving rise to soluble and transmembrane proteins which can signal in a paracrine or a juxtacrine manner activating tyrosine-kinase receptors belonging to the ErbB family.
Transmembrane NRG1 isoforms are expressed by axons of the peripheral nerves and play an important role in the myelination during the development and in the remyelination following an injury. Soluble NRG1 isoforms are released by Schwann cells and play an important role in their de-differentiation, proliferation and survival after nerve injury.
During the last years we focused our attention on the different isoforms of this ligand, discriminating, by quantitative real time PCR, not only between soluble and transmembrane, but also among type α and type β, type a, b or c isoforms, which confer to the cells different signaling properties.
We demonstrated that different soluble NRG1 isoforms are highly over-expressed in the distal portion of the nerve immediately after nerve crush or after nerve transection followed by immediate repair.
Nevertheless, when the injury is more severe and the nerve gap is repaired by tubulization to bridge the proximal and the distal nerve stumps, NRG1 up-regulation is two-week delayed.
Moreover, when for clinical reasons nerve repair is delayed,thedistal portion of thenerve undergo chronic degeneration, NRG1 expression is irreversibly decreased and after nerve repair its expression level is not restored.
Because NRG1 decrease or deficiency might negatively affect nerve regeneration, we are developing new strategies to supply soluble NRG1 to the hollow tube used for immediate or delayed nerve repair. In collaboration with bioengineers, we are developing hydrogels and biocompatible fibers enriched with recombinant growth factors to be used as internal fillers of chitosan tubes.
Moreover, we demonstrated that skeletal muscle fibers release soluble NRG1 isoforms and we are successfully using this autologous material as a filler of hollow tubes to supply soluble NRG1 and compensate for NRG1 deficiency after immediate or delayed repair.
To investigate the role of NRG1 in Schwann cell response to nerve injury, in collaboration with the Molecular Biotechnology Center, we performed a RNA deep sequencing analysis, showing that soluble NRG1 regulates genes involved in Schwann cell de-differentiation from a myelination to a repair phenotype, thus suggesting that therapies with recombinant NRG1 should be restricted to the early phases after nerve injury, to promote Schwann cell de-differentiation and to not inhibit the remyelination process.
Furthermore, in an animal model of chronic demyelinating neuropathy, we found a chronic over-expression of soluble NRG1. If NRG1 over-expression will be confirmed also in human neuropathic nerves, a therapeutic approach aimed to inhibit the signal transduction pathways driven by NRG1 might be developed.
In parallel, we focused our attention also on the role played by NRG1 in controlling neuronal migration in the brain. We found that interneurons migrating from the subventricular zone to the olfactory bulb or from the median ganglionic eminence to the cortex, express different isoforms of the NRG1 receptor ErbB4 and we demonstrated in vitro that neuronal progenitors expressing different ErbB4 isoforms migrate following stimulation with both NRG1α or NRG1β.
Gelatin-based hydrogel for vascular endothelial growth factor release in peripheral nerve tissue engineering. Gnavi S, di Blasio L, Tonda-Turo C, Mancardi A, Primo L, Ciardelli G, Gambarotta G, Geuna S, Perroteau I. Journal of Tissue Engineering and Regenerative Medicine (2017) 11:459-470. doi: 10.1002/term.1936
The Neuregulin1/ErbB system is selectively regulated during peripheral nerve degeneration and regeneration. Ronchi G, Haastert-Talini K, Fornasari BE, Perroteau I, Geuna S, Gambarotta G. European Journal of Neuroscience (2016) 43:351-64. doi: 10.1111/ejn.12974
Neuregulin1 alpha activates migration of neuronal progenitors expressing ErbB4. Fornasari BE, El Soury M, De Marchis S, Perroteau I, Geuna S, Gambarotta G. Molecular and Cellular Neuroscience (2016) 77:87-94. doi: 10.1016/j.mcn.2016.10.008
Local delivery of the Neuregulin1 receptor ecto-domain (ecto-ErbB4) has a positive effect on regenerated nerve fiber maturation. Gambarotta G, Pascal D, Ronchi G, Morano M, Jager SB, Moimas S, Zentilin L, Giacca M, Perroteau I, Tos P, Geuna S, Raimondo S. Gene Therapy (2015) 22:901-7. doi: 10.1038/gt.2015.46
Identification and validation of suitable housekeeping genes for normalizing quantitative real-time PCR assays in injured peripheral nerves. Gambarotta G, Ronchi G, Friard O, Galletta P, Perroteau I, Geuna S. PLoS One (2014) 9(8):e105601. doi: 10.1371/journal.pone.0105601