Lack of effects of transforming growth factor-alpha gene knockout on peripheral nerve regeneration may result from compensatory mechanisms

Transforming growth factor-alpha (TGF-alpha), previously identified as a ma jor member of the epidermal growth factor (EGF) family of growth factors, p lays a role in proliferation, differentiation, and survival of neuronal and glial precursors and is implicated in development of the nervous system. H owever, its roles in nerve injury-induced responses remain obscure. The cur rent study examined roles of endogenous TGF-alpha in peripheral nerve regen eration using sciatic nerve injury models with TGF-alpha knockout mice. Thr ee weeks after a sciatic nerve crush, no significant differences were found between TGF-alpha wild-type and mutant mice in the number of retrogradely labeled L5 dorsal root ganglion (DRG) sensory neurons and L5 spinal cord mo tor neurons and in the morphology of myelinated regenerating nerve fibers, indicating that TGF-alpha is not essential for sensory and motor nerve rege neration. To assess a possible functional redundancy among TGF-alpha -relat ed ligands in response to a nerve injury, mRNA expression of the EGF family was analyzed by RT-PCR in L4/L5 DRG pools and distal degenerating sciatic nerve segments after sciatic nerve ligation. Prior to and 1 day after ligat ion, there was a higher level of EGF-R mRNA in DRGs and in nerve in TGF-alp ha null mice compared to wild types, and there was an induction of ligand a mphiregulin mRNA in DRGs in mutant mice in place of the TGF-alpha upregulat ion present in wild types. These results indicate that TGF-alpha gene knock out does not affect peripheral nerve regeneration, probably due to a functi onal redundancy within the EGF family through a compensatory expression mec hanism at both the receptor and ligand levels in TGF-alpha knockout mice. ( C) 2001 Academic Press.