Embryonic neuronal death due to neurotrophin and neurotransmitter deprivation occurs independent of APAF-1

Apoptotic protease-activating factor-1 (Apaf-1), dATP, and procaspase-9 for m a multimeric complex that triggers programmed cell death through the acti vation of caspases upon release of cytochrome e from the mitochondria into the cytosol. Although cell death pathways exist that can bypass the require ment for cytochrome c release and caspase activation, several gene knockout studies have shown that the cytochrome c-mediated apoptotic pathway is cri tical for neural development. Specifically, the number of neuronal progenit or cells is abnormally increased in Apaf-1-, caspase-9-, caspase-3-deficien t mice. However, the role of the cytochrome c cell death pathway for apopto sis of postmitotic, differentiated neurons in the developing brain has not been investigated in vivo. In this study we investigated embryonic neuronal cell death caused by trophic factor deprivation or lack of neurotransmitte r release by analyzing Apaf-1/tyrosine kinase receptor A (TrkA) and Apaf-1/ Munc-18 double mutant mice. Histological analysis of the double mutants' br ains (including cell counting and terminal (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) staining) reveals that neuronal cell death caused by t hese stimuli can proceed independent of Apaf-1. We propose that a switch between apoptotic programs (and their respective p roteins) characterizes the transition of a neuronal precursor cell from the progenitor pool to the postmitotic population of differentiated neurons. ( C) 2001 IBRO. Published by Elsevier Science Ltd. All rights reserved.