The key role of Schwann cells in peripheral nerve regeneration has already been reported. One of the most important trophic factors for Schwann cells proliferation is Neuregulin1, which exerts its effects by binding the ErbB2/ErbB3 heterodimer receptor. While the effects of ErbB2 deletion in the peripheral nervous system have already been analyzed, the consequences of its overexpression have not been investigated yet. In this study we investigate the effect of constitutive ErbB2 receptor overexpression on adult mouse median nerve morphology in physiological and regenerative conditions. Stereological assessment of healthy nerves showed no differences between ErbB2-overexpressing mice (BALB-neuT) and wild-type mice (BALB/c): they showed comparable number of myelinated fibers and fiber density, as well as similar myelinated fibers size and myelin thickness. By contrast, the overexpression of ErbB2 appeared to speed up the nerve regeneration after a median nerve crush injury, as shown by a faster functional motor recovery. Morphometric evaluation performed 28 days after the injury revealed a significant higher number of regenerated myelinated fibers with a thinner axon and fiber diameter and myelin sheath in BALB-neuT. Moreover, quantitative real time PCR analysis was performed two days after the crush injury in order to analyze the expression level of all ErbB family members and of the different NRG1 isoforms; all the ErbB receptors and the transmembrane (type III) Neuregulin 1 isoforms were decreased in both BALB/c and in BALB-neuT animals. On the other hand, the expression of soluble Neuregulin1 isoforms (type I/II, alpha and beta) increased after the injury and, intriguingly, the expression level in BALB-neuT mice was significantly higher than in wild-type animals. Altogether, these results suggest that constitutional ErbB2 receptor over-expression does not influence the physiological development of peripheral nerves, while it improves nerve regeneration following traumatic injury, possibly strengthening the up-regulation of soluble NRG1 isoforms.
The effect of constitutive ErbB2 receptor overexpression on adult mouse median nerve morphology in physiological and regenerative conditions
RONCHI, GIULIA;GAMBAROTTA, Giovanna;DI SCIPIO, FEDERICA;SALAMONE, PAOLINA;SPRIO, ANDREA ELIO;CAVALLO, Federica;PERROTEAU, Isabelle;BERTA, Giovanni Nicolao;GEUNA, Stefano
2012-01-01
Abstract
The key role of Schwann cells in peripheral nerve regeneration has already been reported. One of the most important trophic factors for Schwann cells proliferation is Neuregulin1, which exerts its effects by binding the ErbB2/ErbB3 heterodimer receptor. While the effects of ErbB2 deletion in the peripheral nervous system have already been analyzed, the consequences of its overexpression have not been investigated yet. In this study we investigate the effect of constitutive ErbB2 receptor overexpression on adult mouse median nerve morphology in physiological and regenerative conditions. Stereological assessment of healthy nerves showed no differences between ErbB2-overexpressing mice (BALB-neuT) and wild-type mice (BALB/c): they showed comparable number of myelinated fibers and fiber density, as well as similar myelinated fibers size and myelin thickness. By contrast, the overexpression of ErbB2 appeared to speed up the nerve regeneration after a median nerve crush injury, as shown by a faster functional motor recovery. Morphometric evaluation performed 28 days after the injury revealed a significant higher number of regenerated myelinated fibers with a thinner axon and fiber diameter and myelin sheath in BALB-neuT. Moreover, quantitative real time PCR analysis was performed two days after the crush injury in order to analyze the expression level of all ErbB family members and of the different NRG1 isoforms; all the ErbB receptors and the transmembrane (type III) Neuregulin 1 isoforms were decreased in both BALB/c and in BALB-neuT animals. On the other hand, the expression of soluble Neuregulin1 isoforms (type I/II, alpha and beta) increased after the injury and, intriguingly, the expression level in BALB-neuT mice was significantly higher than in wild-type animals. Altogether, these results suggest that constitutional ErbB2 receptor over-expression does not influence the physiological development of peripheral nerves, while it improves nerve regeneration following traumatic injury, possibly strengthening the up-regulation of soluble NRG1 isoforms.
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