TRANSFORMING GROWTH-FACTOR ALPHA(TGF-ALPHA) EXPRESSION IN DEGENERATING MOTONEURONS OF THE MURINE MUTANT WOBBLER - A NEURONAL SIGNAL FOR ASTROGLIOSIS

The enhanced expression of the trophic factor transforming growth fact or alpha (TGF alpha) in reactive astrocytes following CNS injury sugge sts that TGF alpha has a role in the development of astrogliosis. We e xplored this hypothesis in the murine mutant wobbler, which presents a progressive motoneuronal degeneration associated with an astrogliosis . Evolution of astrogliosis, and expression of TGF alpha precursor (pr o-TGF alpha) and of its receptor were examined ever the course of the disease, using genetically diagnosed animals and immunocytochemical te chniques. We report here that degenerating motoneurons of the cervical spinal cord and a subset of astrocytes express pro-TGF alpha, prior t o the onset of astrogliosis, when the first clinical manifestations of the disease are observed at 4 weeks of age. TGF alpha expression appe ared strongly correlated with motoneuronal degeneration. All pro-TGF a lpha-immunoreactive neurons exhibited a degenerative morphology, and t he number of pro-TGF alpha-immunoreactive neurons increased with the p rogression of the disease. At the glial level, we observed that astrog liosis was a transitory phenomenon in the wobbler mice, developing in coordination with the motoneuronal expression of pro-TGF alpha. Astrog liosis became evident in 8-week-old wobbler mice, when the number of p ro-TGF alpha-immunoreactive motoneurons was maximal, and regressed in older mutant mice in correlation with the disappearance of pro-TGF alp ha-immunoreactive motoneurons. Furthermore, TGF alpha/EGF receptor imm unoreactivity was exclusively localized in a subset of reactive astroc ytes, its expression following closely the course of the astrogliosis. These data show that TGF alpha synthesis by the affected motoneurons is an early event in the course of the wobbler disease, and suggest a role for TGF alpha as a neuronal inducer of astrocytic reactivity.