Abstract
In a transgenic mice (BALB-neuT) over-expressing ErbB2 receptor, we investigated the adult mouse median nerve in physiological and pathological conditions. Results showed that, in physiological conditions, the grip function controlled by the median nerve in BALB-neuT mice was similar to wild-type (BALB/c). Stereological assessment of ErbB2-overexpressing intact nerves revealed no difference in number and size of myelinated fibers compared to wild-type mice. By contrast, after a nerve crush injury, the motor recovery was significantly faster in BALB-neuT compared to BALB/c mice. Moreover, stereological assessment revealed a significant higher number of regenerated myelinated fibers with a thinner axon and fiber diameter and myelin thickness in BALB-neuT mice. At day-2 post-injury, the level of the mRNAs coding for all the ErbB receptors and for the transmembrane (type III) Neuregulin 1 (NRG1) isoforms significantly decreased in both BALB/c and BALB-neuT mice, as shown by quantitative real time PCR. On the other hand, the level of the mRNAs coding for soluble NRG1 isoforms (type I/II, alpha and beta) increased at the same post-traumatic time point though, intriguingly, this response was significantly higher in BALB-neuT mice with respect to BALB/c mice. Altogether, these results suggest that constitutive ErbB2 receptor over-expression does not influence the physiological development of peripheral nerves, while it improves nerve regeneration following traumatic injury, possibly through the up-regulation of soluble NRG1 isoforms.
Highlights
Peripheral nerve regeneration after a traumatic injury is regulated by the combined action of many factors [1]
ErbB2 null mutant mice die at midgestation because of heart malformation [46] but important alterations of nervous system occur [47]
Morris and co-workers [48] demonstrated that Schwann cell precursors are present and are proliferative in the dorsal root ganglia of transgenic mice lacking ErbB2/ErbB3, but they fail to migrate to the periphery
Summary
Peripheral nerve regeneration after a traumatic injury is regulated by the combined action of many factors [1]. One interesting candidate for the regulation of Schwann cell proliferation is the tyrosine kinase receptor ErbB2 ( called HER-2 or Neu), which belongs to the epidermal growth factor (EGF) receptor family [7,8,9,10]. This receptor is involved in the signal transduction pathways leading to physiologic processes, such as embryogenesis, cell proliferation, and apoptosis [11] and in regenerative processes concerning nerve [12], heart [13], pancreas [14]. Genetic evidence shows that ErbB2 participates in the transduction of signals downstream a family of ligands of the EGF family known as neuregulins [22]
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