Programmed cell death is a mechanism by which organisms dispose of unwanted cells, and it is thought to be an important process in organogenesis. We have already reported the role of caspase-3 in the developing metanephros. While caspase-3 is thought to be positioned downstream of the caspase-activating cascade, the upstream caspase for programmed cell death in the developing kidney is still unknown. In an attempt to identify it, we blocked caspase activity in metanephric explants with caspase inhibitors. Administration of a caspase-9 inhibitor (Ac-IETD-CHO) effectively prevented both ureteric bud branching and nephrogenesis, the same as a caspase-3 inhibitor (Ac-DEVD-CHO). On the other hand, administration of a caspase-8 inhibitor (Ac-LETD-CHO) did not inhibit ureteric bud branching or nephrogenesis. Apaf-1, which executes programmed cell death in the caspase-9-related pathway, was detected in the cells exhibiting caspase-9 activity, and our results suggest that Apaaf-1/caspase-9 activates caspase-3 in kidney organogenesis.

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