Epistatic and independent functions of Caspase-3 and Bcl-X-L in developmental programmed cell death

The number of neurons in the mammalian brain is determined by a balance bet ween cell proliferation and programmed cell death. Recent studies indicated that Bcl-X-L prevents, whereas Caspase-3 mediates, cell death in the devel oping nervous system, but whether Bcl-X-L directly blocks the apoptotic fun ction of Caspase-3 in vivo is not known. To examine this question. we gener ated bcl-x/caspase-3 double mutants and found that caspase-3 deficiency abr ogated the increased apoptosis of postmitotic neurons but not the increased hematopoietic cell death and embryonic lethality caused by the bcl-x mutat ion. In contrast, caspase-3, but not bcl-x, deficiency changed the normal i ncidence of neuronal progenitor cell apoptosis, consistent with the lack of expression of Bcl-X-L in the proliferative population of the embryonic cor tex. Thus, although Caspase-3 is epistatically downstream to Bcl-X-L in pos tmitotic neurons, it independently regulates apoptosis of neuronal founder cells. Taken together, these results establish a role of programmed cell de ath in regulating the size of progenitor population in the central nervous system, a function that is distinct from the classic role of cell death in matching postmitotic neuronal population with postsynaptic targets.