THYROID-HORMONE PROMOTES BCL-2 EXPRESSION AND PREVENTS APOPTOSIS OF EARLY DIFFERENTIATING CEREBELLAR GRANULE NEURONS

Programmed cell death is a basic cellular process that has aroused muc h interest in recent years. Like immune cells, cultures of cerebellar granule neurons are very homogeneous and provide a unique opportunity for quantifying by flow cytometry one form of programmed cell death in the CNS, the apoptosis, and for studying its regulation by neurotroph ic factors. We found that thyroid hormone promoted postmitotic surviva l by preventing the apoptosis of newly formed and early differentiated granule neurons in a dose-dependent manner. This regulation could be through the protein bcl-2, which is known to prevent cell death. This protein was present at ail stages of granule neuron differentiation an d appeared to be developmentally regulated. It was underexpressed in a poptotic granule neurons. The protein content of the cerebellum in hyp othyroid rats was drastically reduced. In contrast, thyroid hormone ca used a marked dose-dependent increase in the amounts of this protein i n granule neuron cultures. The possibility that thyroid hormone may be directly or indirectly required to promote cell survival is discussed , in terms of the hormone control of the local delivery of neurotrophi ns, such as NGF and NT-3, as well as the expression of their low affin ity receptors, gp75. We suggest that thyroid hormone has a permissive action on the developing CNS.