title: Embryonic neuronal death due to neurotrophin and neurotransmitter deprivation occurs independent of Apaf-1.
abstract: Apoptotic protease-activating factor-1 (Apaf-1), dATP, and procaspase-9 form a multimeric complex that triggers programmed cell death through the activation of caspases upon release of cytochrome c from the mitochondria into the cytosol. Although cell death pathways exist that can bypass the requirement for cytochrome c release and caspase activation, several gene knockout studies have shown that the cytochrome c-mediated apoptotic pathway is critical for neural development. Specifically, the number of neuronal progenitor cells is abnormally increased in Apaf-1-, caspase-9-, caspase-3-deficient mice. However, the role of the cytochrome c cell death pathway for apoptosis 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 neurotransmitter release by analyzing Apaf-1/tyrosine kinase receptor A (TrkA) and Apaf-1/Munc-18 double mutant mice. Histological analysis of the double mutants' brains (including cell counting and terminal (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) staining) reveals that neuronal cell death caused by these stimuli can proceed independent of Apaf-1. We propose that a switch between apoptotic programs (and their respective proteins) characterizes the transition of a neuronal precursor cell from the progenitor pool to the postmitotic population of differentiated neurons.
authors.affiliation: Department of Molecular Genetics, The University of Texas Southwestern Medical Center, 5323 Harry Hines Building, Dallas, TX 75390, USA.
authors.forename: N
authors.initials: N
authors.lastname: Honarpour
authors.forename: K
authors.initials: K
authors.lastname: Tabuchi
authors.forename: J M
authors.initials: JM
authors.lastname: Stark
authors.forename: R E
authors.initials: RE
authors.lastname: Hammer
authors.forename: T C
authors.initials: TC
authors.lastname: Südhof
authors.forename: L F
authors.initials: LF
authors.lastname: Parada
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.forename: J A
authors.initials: JA
authors.lastname: Richardson
authors.forename: J
authors.initials: J
authors.lastname: Herz
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D053477:Apoptotic Protease-Activating Factor 1; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D003574:Cytochrome c Group / Q000378:metabolism; D017950:Ganglia, Sensory / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D051938:Munc18 Proteins; D009414:Nerve Growth Factors / Q000378:metabolism*; D009419:Nerve Tissue Proteins; D009420:Nervous System / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D020917:Receptor, trkA / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D033921:Vesicular Transport Proteins
chemical_list: C506593:Apaf1 protein, mouse; D053477:Apoptotic Protease-Activating Factor 1; D003574:Cytochrome c Group; D051938:Munc18 Proteins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D011506:Proteins; D033921:Vesicular Transport Proteins; D020917:Receptor, trkA; D020169:Caspases