Genetic variance modifies apoptosis susceptibility in mature oocytes via alterations in DNA repair capacity and mitochondrial ultrastructure.
Although the identification of specific genes that regulate apoptosis has been a topic of intense study, little is known of the role that background genetic variance plays in modulating cell death. Using germ cells from inbred mouse strains, we found that apoptosis in mature (metaphase II) oocytes is affected by genetic background through at least two different mechanisms. The first, manifested in AKR/J mice, results in genomic instability. This is reflected by numerous DNA double-strand breaks in freshly isolated oocytes, causing a high apoptosis susceptibility and impaired embryonic development following fertilization. Microinjection of Rad51 reduces DNA damage, suppresses apoptosis and improves embryonic development. The second, manifested in FVB mice, results in dramatic dimorphisms in mitochondrial ultrastructure. This is correlated with cytochrome c release and a high apoptosis susceptibility, the latter of which is suppressed by pyruvate treatment, Smac/DIABLO deficiency, or microinjection of 'normal' mitochondria. Therefore, background genetic variance can profoundly affect apoptosis in female germ cells by disrupting both genomic DNA and mitochondrial integrity.
Perez
G I
GI
Vincent Center for Reproductive Biology, Vincent Obstetrics and Gynecology Service, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02114, USA. perezg@partners.org
Acton
B M
BM
Jurisicova
A
A
Perkins
G A
GA
White
A
A
Brown
J
J
Trbovich
A M
AM
Kim
M-R
MR
Fissore
R
R
Xu
J
J
Ahmady
A
A
D'Estaing
S G
SG
Li
H
H
Kagawa
W
W
Kurumizaka
H
H
Yokoyama
S
S
Okada
H
H
Mak
T W
TW
Ellisman
M H
MH
Casper
R F
RF
Tilly
J L
JL
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology; D045304:Cytochromes c / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D005260:Female; D014644:Genetic Variation; D051379:Mice; D008806:Mice, Inbred AKR; D008815:Mice, Inbred Strains; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure*; D024101:Mitochondrial Proteins / Q000378:metabolism / Q000502:physiology; D009865:Oocytes / Q000378:metabolism / Q000502:physiology*; D051135:Rad51 Recombinase / Q000378:metabolism / Q000502:physiology
D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C499605:Diablo protein, mouse; D024101:Mitochondrial Proteins; D045304:Cytochromes c; D051135:Rad51 Recombinase