Adult Apaf-1-deficient mice exhibit male infertility.
Release of cytochrome c from the mitochondria, and subsequent binding to apoptotic protease-activating factor-1 (Apaf-1), is a key trigger of apoptotic events. A complex composed of Apaf-1, dATP, and cytochrome c activates a series of cytoplasmic proteases called caspases, leading to apoptotic cell death. We have disrupted the Apaf-1 gene in the mouse. Like previous reports on this knockout model, we find that most Apaf-1 mutants die perinatally and frequently exhibit exencephaly and cranioschesis. We additionally find that the neural lesions that develop in the knockout are due to an excess of neural progenitor cells that manifests as early as embryonic day 9.5 in development. In contrast to previous reports on the Apaf-1 knockout mice, we find that 5% of the mutants successfully survive to adulthood. In these survivors, the brain develops normally, but in males, there is degeneration of spermatogonia resulting in the virtual absence of sperm. Thus, cytochrome c-mediated apoptosis is not absolutely required for normal neural development, but is essential for spermatogenesis. These findings strongly suggest that alternative apoptotic pathways work in conjunction with and parallel to Apaf-1 and can modify its effect on programmed cell death.
Honarpour
N
N
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75235, USA.
Du
C
C
Richardson
J A
JA
Hammer
R E
RE
Wang
X
X
Herz
J
J
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D053477:Apoptotic Protease-Activating Factor 1; D001483:Base Sequence; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D017931:DNA Primers; D004789:Enzyme Activation; D018507:Gene Expression Regulation, Developmental; D007248:Infertility, Male / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D013094:Spermatozoa / Q000166:cytology / Q000201:enzymology / Q000378:metabolism
C506593:Apaf1 protein, mouse; D053477:Apoptotic Protease-Activating Factor 1; D003574:Cytochrome c Group; D017931:DNA Primers; D011506:Proteins; D000255:Adenosine Triphosphate; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases