bax Deficiency Prevents the Increased Cell Death of Immature Neurons in bcl-x-Deficient Mice

Abstract

The intracellular balance between pro- and antiapoptotic members of the Bcl-2 gene family is thought to regulate cell death. Targeted disruption of bcl-x, a death repressing member, causes massive cell death of immature neurons in the developing mouse CNS, whereas targeted disruption of bax, a proapoptotic member, blocks the death of specific populations of sympathetic and motor neurons. In the present study, mice deficient in both Bcl-x L and Bax (bcl-x−/−/bax−/−) are used to examine the relative significance and potential interactions of Bcl-x L and Bax during early CNS development.bcl-x−/−/bax−/−mice demonstrate greatly reduced levels of apoptosis both in vivo and in vitro compared with the CNS of Bcl-x L-deficient mice, as assessed by histology and terminal deoxytransferase-mediated deoxyuridine triphosphate nick end-labeling. Bax-deficient mice, however, contain occasional apoptotic cells in the developing CNS, and cultures of bax-deficient telencephalic cells demonstrate similar levels of apoptosis as wild-type cultures. These results suggest that Bax critically interacts with Bcl-x L to regulate survival of immature neurons, but indicate that other cell death regulating proteins, in addition to Bcl-x L and Bax, also function during CNS development.