Institutes
Axo-glia interaction
Myelin, a remarkable highly specialized membrane enwrapping the axons in Central (CNS) and Peripheral Nervous system (PNS), is crucial to ensure efficient propagation of the electric impulse, to execute complex CNS functions, and to maintain the integrity of the axons: ultimately neuronal survival. Alteration in myelination can have dramatic consequences spanning from reduction of nerve conduction velocity to neuronal cell death. Myelin is formed and maintained by continuous communication between axons and myelinating glial cells, Schwann cells in the PNS and oligodendrocytes in the CNS. This continuous communication is necessary not only for the correct development of the nervous system but to ensure a permanent and efficient transmission of the electric impulse. While it was known that neurons provide trophic and metabolic support to glial cells, thus promoting proliferation, survival and differentiation of myelinating glia, only more recent studies have highlighted the importance of glial cells in neuronal survival and in providing the required metabolic support to the axons. Indeed, in the absence of glial cells, axons degenerate leading eventually to neuronal cell death and permanent damage of the nervous system. Thus, a better understanding of the processes involved in axo-glial interaction is crucial to develop effective treatments for demyelinating disorders.
Research activity
Our main interest is to investigate the cross talk between glial cells and axons in development in PNS and CNS and to study how it is impaired in pathological settings.
We previously showed that Neuregulin 1 (NRG1) type III is a key instructive signal for PNS myelination. Further, we demonstrated that the α-secretase TACE post-transcriptionally regulates NRG1 type III activity. More recently we also showed that the γ-secretase processing of NRG1 type III upregulates the expression of Prostaglandin D2 synthase and activates a new pathway promoting PNS myelin formation and maintenance.
Differently form the PNS, in the CNS several factors contribute to myelin sheet formation and maintenance. Importantly, the majority of these growth factors are also subjected to regulated secretases’ processing. Collectively, our studies suggest the existence of post-transcriptional mechanism(s) regulating myelin formation and axonal survival and identify secretases as a potential therapeutic target to modulate myelination and possibly neuronal survival.
We previously showed that Neuregulin 1 (NRG1) type III is a key instructive signal for PNS myelination. Further, we demonstrated that the α-secretase TACE post-transcriptionally regulates NRG1 type III activity. More recently we also showed that the γ-secretase processing of NRG1 type III upregulates the expression of Prostaglandin D2 synthase and activates a new pathway promoting PNS myelin formation and maintenance.
Differently form the PNS, in the CNS several factors contribute to myelin sheet formation and maintenance. Importantly, the majority of these growth factors are also subjected to regulated secretases’ processing. Collectively, our studies suggest the existence of post-transcriptional mechanism(s) regulating myelin formation and axonal survival and identify secretases as a potential therapeutic target to modulate myelination and possibly neuronal survival.
Mazzara P, Massimino L, Pellegatta M, Ronchi G, Ricca A, Iannielli A, Giannelli S, Cursi M, Cancellieri C, Sessa A, Del Carro U, Quattrini A, Geuna S, Gritti A, Taveggia C, Broccoli V. Two factor based reprogramming of rodent and human fibroblasts into myelinogenic Schwann cells. Nature Communications 2017;8:14088.
Bolino A, Piguet F, Alberizzi V, Pellegatta M, Rivellini C, Guerrero-Valero M, Noseda R, Brombin C, Nonis A, D'Adamo P, Taveggia C, Previtali SC. Niacin-mediated TACE activation ameliorates CMT neuropathies with focal hypermyelination. EMBO Mol Med 2016; 8:1438-1454.
Taveggia C. Schwann cells – axon interaction in myelination. Current Opinion in Neurobiology 2016; 39:24-29.
Poitelon Y, Bogni S, Matafora V, Della-Flora Nunes G, Hurley E, Ghidinelli M, Katzenellenbogen BS, Taveggia C, Silvestri N, Bachi A, Sannino A, Wrabetz L, Feltri ML. Spatial mapping of juxtacrine axo-glial interactions identifies novel molecules in peripheral myelination. Nature Communications 2015; 6:8303.
Trimarco A, Forese MG, Alfieri V, Lucente A, Brambilla P, Dina G, Pieragostino D, Sacchetta P, Urade Y, Boizet-Bonhoure B, Martinelli Boneschi F, Quattrini A, Taveggia C. Prostaglandin D2 synthase-GPR44: a signaling axis in PNS myelination. Nature Neuroscience 2014; 17:1682-1692.
Laterza C, Merlini A, De Feo D, Ruffini F, Menon R, Onorati M, Fredrickx E, Muzio L, Lombardo A, Comi G, Quattrini A, Taveggia C, Farina C, Cattaneo E, Martino G. iPSC-derived neural precursors exert a neuroprotective role in immune-mediated demyelination via the secretion of LIF. Nature Communications 2013; 4:2597.
Velanac V, Unterbarnscheidt T, Hinrichs W, Gummert MN, Fischer TM, Trimarco A, Brivio V, Taveggia C, Willem M, Haass C, Möbius W, Nave KA, Schwab MH. BACE1 processing of NRG1 type III produces a myelin-inducing signal but is not essential for the stimulation of myelination. Glia 2012; 60:203-217.
La Marca R, Cerri F, Horiuchi K, Bachi A, Feltri ML, Wrabetz L, Blobel CP, Quattrini A., Salzer JL and Taveggia C. ADAM17/TACE inhibits Schwann cell myelination. Nature Neuroscience 2011; 14:857-865.
Taveggia C, Feltri ML and Wrabetz L. Signals to promote myelin formation and repair. Nature Reviews Neurology 2010; 6:276-287.
Taveggia C, Zanazzi, G, Petrylak A, Yano H, Rosenbluth J, Einheber S, Xu X, Esper MR, Loeb JA, Shrager P, Chao MV, Falls DL, Role L and Salzer JL. Neuregulin-1 type III determines the ensheathment fate of axons. Neuron 2005; 47:681-694.
