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

<jats:p> The number of neurons in the mammalian brain is determined by a balance between cell proliferation and programmed cell death. Recent studies indicated that Bcl-X <jats:sub>L</jats:sub> prevents, whereas Caspase-3 mediates, cell death in the developing nervous system, but whether Bcl-X <jats:sub>L</jats:sub> directly blocks the apoptotic function of Caspase-3 <jats:italic>in vivo</jats:italic> is not known. To examine this question, we generated <jats:italic>bcl-x</jats:italic> / <jats:italic>caspase-3</jats:italic> double mutants and found that <jats:italic>caspase-3</jats:italic> deficiency abrogated the increased apoptosis of postmitotic neurons but not the increased hematopoietic cell death and embryonic lethality caused by the <jats:italic>bcl-x</jats:italic> mutation. In contrast, <jats:italic>caspase-3</jats:italic> , but not <jats:italic>bcl-x</jats:italic> , deficiency changed the normal incidence of neuronal progenitor cell apoptosis, consistent with the lack of expression of Bcl-X <jats:sub>L</jats:sub> in the proliferative population of the embryonic cortex. Thus, although Caspase-3 is epistatically downstream to Bcl-X <jats:sub>L</jats:sub> in postmitotic neurons, it independently regulates apoptosis of neuronal founder cells. Taken together, these results establish a role of programmed cell death 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. </jats:p>