Cultures of neurons from rat embryos have been shown previously to express high levels of a unique form of pp60c-src Prugge et al(1985): Nature 316:524-5261, the cellular homologue of the transforming protein of Rous sarcoma virus. This altered form of pp60c-src, designated pp6OC-"'"(+', displays a retarded electrophoretic mobility due to a structural alteration within the aminoterminal region of the molecule mrugge et al, 19851. In order to investigate the distribution and possible role of pp60c-src'+' in intact brain, we have examined the expression of pp60c"rc(+' in extracts from developing cerebella from wild-type mice and mutant mice that display progressive degeneration of specific classes of cerebellar neurons. The loss of generally correlated with the loss of granule cells and Purkinje cells from the cerebella of mice carrying the staggerer (sg/sg) and Lurcher ( k l + ) mutations, with the most pronounced changes observed in cerebella from the more severely affected sg/sg mice. The expression of pp60c-s"(+' in weaver wvlwv mice is qualitatively and quantitatively quite different. From the earliest time points, there was a significant reduction in the levels of pp60c-src(+' , with no further loss of this form during the period of maximal neuronal differentiation. This suggests an early, predegenerative absence of pp60c-src(+' in this mutant strain, which is defective in granule-cell migration.