Cellular and Molecular Biology Group
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.
Prodotti della ricerca
Fornasari B E , Carta G , Gambarotta G , Raimondo S (2020)
Natural-Based Biomaterials for Peripheral Nerve Injury Repair.
Ronchi Giulia, Gambarotta Giovanna, Morano Michela, Fregnan Federica, Pugliese Pierpaolo, Tos Pierluigi, Geuna Stefano, Haastert-Talini Kirsten (2020)
Critical analysis of the value of the rabbit median nerve model for biomedical research on peripheral nerve grafts.
Benedetta E Fornasari, Marwa El Soury, Giulia Nato, Alessia Fucini, Giacomo Carta, Giulia Ronchi, Alessandro Crosio, Isabelle Perroteau, Stefano Geuna, Stefania Raimondo, Giovanna Gambarotta (2020)
Fibroblasts colonizing nerve conduits express high levels of soluble Neuregulin1, a factor promoting Schwann cell dedifferentiation.
Gambarotta G , Raimondo S , Udina E , Phillips J B , Haastert-Talini K (2019)
Editorial: Peripheral Nerve Regeneration.
Crosio, Alessandro, Fornasari, Benedetta, Gambarotta, Giovanna, Geuna, Stefano, Raimondo, Stefania, Battiston, Bruno, Tos, Pierluigi, Ronchi, Giulia (2019)
Chitosan tubes enriched with fresh skeletal muscle fibers for delayed repair of peripheral nerve defects.
Giulia Ronchi, Michela Morano, Federica Fregnan, Pierfrancesco Pugliese, Alessandro Crosio, Pierluigi Tos, Stefano Geuna, Kirsten Haastert-Talini, Giovanna Gambarotta (2019)
The median nerve injury model in pre-clinical research – a critical review on benefits and limitations.
El Soury Marwa, Gambarotta Giovanna (2019)
Soluble neuregulin-1 (NRG1): a factor promoting peripheral nerve regeneration by affecting Schwann cell activity immediately after injury.
Giovanna Gambarotta, Kirsten Haastert-Talini, Esther Udina, Stefania Raimondo, James Phillips (2019)
Peripheral nerve regeneration.
Marwa El Soury, Benedetta Elena Fornasari, Michela Morano, Elio Grazio, , , Giulia Ronchi, Danny Incarnato, Mario Giacobini, Stefano Geuna, Paolo Provero, Giovanna Gambarotta (2018)
Soluble Neuregulin1 down-regulates myelination genes in Schwann cells.
Fornasari, Benedetta Elena, Ronchi, Giulia, Pascal, Davide, Visigalli, Davide, Capodivento, Giovanna, Nobbio, Lucilla, Perroteau, Isabelle, Schenone, Angelo, Geuna, Stefano, Gambarotta, Giovanna* (2018)
Soluble Neuregulin1 is strongly up-regulated in the rat model of Charcot-Marie-Tooth 1A disease.
Sara Gnavi, Michela Morano, Benedetta Fornasari, Claudio Riccobono, Chiara Tonda-Turo, Marco Zanetti, Gianluca Ciardelli, Giovanna Gambarotta, Isabelle Perroteau, Stefano Geuna, Stefania Raimondo (2018)
Combined Influence of Gelatin Fibre Topography and Growth Factors on Cultured Dorsal Root Ganglia Neurons.
Giulia Ronchi, Benedetta Elena Fornasari, Alessandro Crosio, , , Claudia Alexandra Budau, Pierluigi Tos, Isabelle Perroteau, Bruno Battiston, , , Stefano Geuna, Stefania Raimondo, Giovanna Gambarotta (2018)
Chitosan Tubes Enriched with Fresh Skeletal Muscle Fibers for Primary Nerve Repair.
Morano Michela, Ronchi Giulia, Nicolò Valentina, Fornasari Benedetta Elena, Crosio Alessandro, Perroteau Isabelle, Geuna Stefano, Gambarotta Giovanna, Raimondo Stefania (2018)
Modulation of the Neuregulin 1/ErbB system after skeletal muscle denervation and reinnervation.