DEVELOPMENTAL REGULATION OF APOPTOSIS IN DORSAL-ROOT GANGLION NEURONS

The survival of dorsal root ganglion (DRG) neurons, both in vivo and i n vitro, is dependent on the availability of nerve growth factor (NGF) for a transient period early in development after which these neurons become independent of NGF for survival. The precise molecular mechani sm by which developing DRG neurons gain independence from NGF has not been determined. We used an in vitro model of DRG neuronal development to test hypotheses that independence from NGF in mature DRG neurons c ould be caused by developmental regulation of either elements of the N GF withdrawal signal transduction pathway or of proteins important for activation of the apoptosis output pathway. Interruption of phosphoti dylinositol-3 kinase activation, by treatment with the specific inhibi tor LY294002, resulted in apoptosis in immature but not mature DRG neu rons in a manner similar to that observed with NGF withdrawal. Further downstream along the signal transduction pathway, c-JUN phosphorylati on occurred in both immature and mature DRG neurons after NGF withdraw al or treatment with LY294002, despite the fact that the older neurons did not undergo apoptosis. In contrast, the ratio of expression of th e proapoptotic gene bax to antiapoptotic gene bcl-x(L) was many times higher in immature than mature neurons, both in vivo and in vitro. Tak en together, these results strongly suggest that developmental regulat ion of NGF withdrawal-induced apoptosis in DRG occurs via control of t he relative level of expression of members of the bcl-2 gene family.