Transforming Growth Factor a! (TGFa) Expression in Degenerating Motoneurons of the Murine Mutant Wobbler: A Neuronal Signal for Astrogliosis?

The enhanced expression of the trophic factor transforming growth factor (Y (TGFa) in reactive astrocytes following CNS injury suggests that TGFcI has a role in the development of astrogliosis. We explored this hypothesis in the murine mutant wobbler, which presents a progressive motoneuronal degeneration associated with an astrogliosis. Evolution of astrogliosis, and expression of TGF~Y precursor (pro-TGFa) and of its receptor were examined over the course of the disease, using genetically diagnosed animals and immunocytochemical techniques. We report here that degenerating motoneurons of the cervical spinal cord and a subset of astrocytes express pro-TGFa, prior to the onset of astrogliosis, when the first clinical manifestations of the disease are observed at 4 weeks of age. TGFa expression appeared strongly correlated with motoneuronal degeneration. All pro-TGFa-immunoreactive neurons exhibited a degenerative morphology, and the number of pro-TGFa-immunoreactive neurons increased with the progression of the disease. At the glial level, we observed that astrogliosis was a transitory phenomenon in the wobbler mice, developing in coordination with the motoneuronal expression of pro-TGFa. Astrogliosis became evident in 6-week-old wobbler mice, when the number of pro-TGFa-immunoreactive motoneurons was maximal, and regressed in older mutant mice in correlation with the disappearance of pro-TGFa-immunoreactive motoneurons. Furthermore, TGF~YIEGF receptor immunoreactivity was exclusively localized in a subset of reactive astrocytes, its expression following closely the course of the astrogliosis. These data show that TGFa synthesis by the affected motoneurons is an early event in the course of the wobbler disease, and suggest a role for TGFa as a neuronal inducer of astrocytic reactivity. [