Epidermal growth factor and transforming growth factor-alpha gene expression in the normal and neurodegenerate murine central nervous system.

摘要

A solution hybridization-ribonuclease protection assay was developed to identify epidermal growth factor (EGF) mRNA in mouse brain and to compare the regional and developmental levels of EGF gene expression in the CNS with those of transforming growth factor-{dollar}alpha{dollar} (TGF-{dollar}alpha){dollar}, a structurally-related peptide believed to utilize the EGF receptor in vivo. Regional analysis revealed co-expression of EGF and TGF-{dollar}alpha{dollar} mRNAs in brainstem, cerebellum, cerebral cortex, hippocampus, basal hypothalamus, olfactory bulb, olfactory tubercle, striatum and thalamus with TGF-{dollar}alpha{dollar} mRNA levels 15-170 times higher than the corresponding regional levels of EGF mRNA. No significant male-female differences in EGF or TGF-{dollar}alpha{dollar} mRNA levels were observed for any region of adult brain. In the pituitary gland, consisting of both endocrine and neural elements, EGF and TGF-{dollar}alpha{dollar} mRNA levels were significantly higher in males. An analysis of growth factor gene expression in the developing CNS revealed the presence of both EGF and TGF-{dollar}alpha{dollar} mRNAs in embryonic mouse brain as early as embryonic day 14 with levels decreasing in the early postnatal period.; An examination of growth factor gene expression in Purkinje cell degeneration (Pcd) mutant cerebellum, characterized by a progressive loss of Purkinje neurons, revealed significantly higher concentrations of EGF and TGF-{dollar}alpha{dollar} mRNAs by 39 and 60 days of age, respectively, when compared to normals. In Pcd mutant olfactory bulbs, in which degenerating nerve fibers are present at {dollar}sim{dollar}13 weeks, EGF mRNA concentrations were above control values at {dollar}sim{dollar}11-12 weeks of age while mutant TGF-{dollar}alpha{dollar} mRNA levels were transiently decreased at {dollar}sim{dollar}9-10 weeks. In the cerebellum of weaver mutants, characterized by severe granule cell losses, EGF and TGF-{dollar}alpha{dollar} mRNA concentrations did not significantly differ from the levels observed in normal mice, while total EGF and TGF-{dollar}alpha{dollar} mRNA content in mutant cerebella were reduced. Altered patterns of expression of EGF and TGF-{dollar}alpha{dollar} mRNAs in Pcd cerebellum, olfactory bulb or weaver cerebellum did not parallel quantitative changes in mRNA for glial fibrillary acidic protein (GFAP). In view of both temporal and quantitative differences in EGF and TGF-{dollar}alpha{dollar} gene expression in the normal and neurodegenerative brain, EGF and TGF-{dollar}alpha{dollar} likely have distinct physiologic roles in the development, maintenance and response to injury of the mammalian CNS.