A central role for ceramide in the age-related acceleration of apoptosis in the female germline.
An age-dependent acceleration of apoptosis occurs in female germ cells (oocytes), and this requires communication between the oocyte and its surrounding somatic (cumulus) cells. Here we show in aged mice that ceramide is translocated from cumulus cells into the adjacent oocyte and induces germ cell apoptosis that can be prevented by sphingosine-1-phosphate. Trafficking of ceramide requires gap junction-dependent communication between the cumulus cells and the oocyte as well as intact lipid rafts. Further, the occurrence of the elevated incidence of apoptosis in oocytes of aged females is concomitant with an enhanced sensitivity of the oocyte to a spike in cytosolic ceramide levels, as well as increased bax mRNA and Bax protein levels. Thus, the force driving the age-related increase in female germ cell death is multifactorial, but changes in the intercellular trafficking of ceramide, along with hypersensitivity of oocytes to ceramide, are key factors in this process.
Perez
Gloria I
GI
Vincent Center for Reproductive Biology, Vincent Obstetrics and Gynecology Service, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA. perezg@msu.edu
Jurisicova
Andrea
A
Matikainen
Tiina
T
Moriyama
Toshitake
T
Kim
Mee-Ran
MR
Takai
Yasushi
Y
Pru
James K
JK
Kolesnick
Richard N
RN
Tilly
Jonathan L
JL
D000375:Aging / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001692:Biological Transport; D002450:Cell Communication; D002478:Cells, Cultured; D002518:Ceramides / Q000032:analysis / Q000172:deficiency / Q000494:pharmacology / Q000502:physiology*; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000737:chemistry; D005260:Female; D005372:Filipin / Q000494:pharmacology; D017629:Gap Junctions / Q000187:drug effects / Q000502:physiology; D006034:Glycyrrhetinic Acid / Q000494:pharmacology; D008246:Lysophospholipids / Q000494:pharmacology; D021962:Membrane Microdomains / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009865:Oocytes / Q000737:chemistry / Q000502:physiology* / Q000648:ultrastructure; D006080:Ovarian Follicle / Q000166:cytology / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000032:analysis / Q000235:genetics
D002518:Ceramides; D008246:Lysophospholipids; D012333:RNA, Messenger; D051028:bcl-2-Associated X Protein; C060506:sphingosine 1-phosphate; C097760:N-palmitoylsphingosine; D005372:Filipin; D045304:Cytochromes c; D013110:Sphingosine; D006034:Glycyrrhetinic Acid