Susceptibility to Cell Death Induced by Mutant SV40 T-Antigen Correlates with Purkinje Neuron Functional Development

Abstract

Purkinje cells are uniquely susceptible to a number of physical, chemical, and genetic insults both during development and in the mature state. We have previously shown that when the postmitotic state of murine Purkinje cells is altered by inactivation of the retinoblastoma tumor susceptibility protein (pRb), immature as well as mature Purkinje cells undergo apoptosis. DNA synthesis and neuronal loss are induced in postmitotic Purkinje cells dependent upon the pRb-binding portion of SV40 large T antigen (T-ag). In the present study, Purkinje cell targeting of a mutant T-ag, PVU, which does not bind pRb, reveals disparate cerebellar phenotypes dependent upon temporal differences in transgene expression. Strong embryonic and postnatal transgene expression in three lines alters Purkinje cell development and function during the second postnatal week, causing ataxia without Purkinje cell loss. In contrast, two other transgenic lines reveal that PVU T-ag expression following normal Purkinje cell maturation causes rapid Purkinje cell degeneration. The second and third postnatal weeks of cerebellar development, which include the major period of synaptogenesis, appear to be the defining stage for the two PVU-induced phenotypes. These data indicate that Purkinje cell death susceptibility varies with developmental stage.