NICO in the top 10 EJN articles written by researchers in Italy

European Journal of Neuroscience
Read one of the top EJN articles written by researchers in Italy!

The European Journal of Neuroscience presented a collection of pioneering and original research and reviews articles in the fields of molecular, cellular, systems, behavioural and cognitive neurosciences free to access until the end of 2018.

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A pubblication by Prof. Stefano Geuna's Research Group is one of the 10 written by researchers in Italy.

European Journal of Neuroscience, 8 July 2015
The Neuregulin1/ErbB system is selectively regulated during peripheral nerve degeneration and regeneration.

Ronchi G ^1,2 , Haastert-Talini K ^3,4 , Fornasari BE ¹ , Perroteau I ^1,5 , Geuna S ^1,2,5 , Gambarotta G ^1,5

The peripheral nervous system has an intrinsic capability to regenerate, crucially related to the ability of Schwann cells (SC) to create a permissive environment, for example, through production of regeneration-promoting neurotrophic factors. Survival, proliferation, migration and differentiation of SC into a myelinating phenotype during development and after injury is regulated by different Neuregulin1 (NRG1) isoforms.

This study investigates the expression of different NRG1 isoforms and of their ErbB receptors in distal rat median nerve samples under regenerating conditions after a mild (crush) and more severe (end-to-end repair) injury and under degenerating condition. The expression of the NRG1/ErbB system was evaluated at mRNA and protein level, and demonstrated to be specific for distinct and consecutive phases following nerve injury and regeneration or the progress in degeneration.

For the first time a detailed analysis of expression profiles not only of soluble and transmembrane NRG1 isoforms, but also of alpha and beta as well as type a, b and c isoforms is presented. The results of mRNA and protein expression pattern analyses were related to nerve ultrastructure changes evaluated by electron microscopy. In particular, transmembrane NRG1 isoforms are differentially regulated and proteolytically processed under regeneration and degeneration conditions. Soluble NRG1 isoforms alpha and beta, as well as type a and b, are strongly upregulated during axonal regrowth, while type c NRG1 isoform is downregulated. This is accompanied by an upregulation of ErbB receptors.

This accurate regulation suggests that each molecule plays a specific role that could be clinically exploited to improve nerve regeneration.

After nerve injury, Neuregulin1 (NRG1) activity is finely regulated both at transcriptional and post-translational level

Different NRG1 isoforms are expressed by different cell types: Transmembrane NRG1 is expressed by axons and finely regulates myelination.It is known that transmembrane NRG1 cleaved by α-secretase (TACE) inhibits myelination, while NRG1 cleaved by β-secretase (BACE) stimulates myelination (NTF=N terminal fragment). By western blot analysis we observed, for the first time, that in the healthy nerve and in the regenerated nerve (which indeed no longer needs myelination activity) transmembrane NRG1 is cleaved by TACE, while in the injured nerve (which on the contrary needs remyelination) transmembrane NRG1 is cleaved by BACE.

Soluble NRG1 is released by Schwann cells, stimulating their dedifferentiation, proliferation and survival. By quantitative real time PCR we demonstrated that different soluble isoforms are strongly up-regulated by Schwann cells immediately after injury.

By electron microscopy analysis it is possible to observe step by step the nerve degeneration (in the cut nerve without repair), and the nerve regeneration (in the cut and repaired nerve).

¹ Department of Clinical and Biological Sciences, University of Torino, Regione Gonzole 10, Orbassano, 10043, Italy.
² Neuroscience Institute of the 'Cavalieri Ottolenghi' Foundation (NICO), University of Torino, Orbassano, Italy.
³ Hannover Medical School, Institute of Neuroanatomy, Hannover, Germany.
⁴ Center for Systems Neuroscience (ZSN), Hannover, Germany.
⁵ Neuroscience Institute of Torino (NIT), University of Torino, Orbassano, Italy.