Mitochondrial degeneration and not apoptosis is the primary cause of embryonic lethality in ceramide transfer protein mutant mice.
Ceramide transfer protein (CERT) functions in the transfer of ceramide from the endoplasmic reticulum (ER) to the Golgi. In this study, we show that CERT is an essential gene for mouse development and embryonic survival and, quite strikingly, is critical for mitochondrial integrity. CERT mutant embryos accumulate ceramide in the ER but also mislocalize ceramide to the mitochondria, compromising their function. Cells in mutant embryos show abnormal dilation of the ER and degenerating mitochondria. These subcellular changes manifest as heart defects and cause severely compromised cardiac function and embryonic death around embryonic day 11.5. In spite of ceramide accumulation, CERT mutant mice do not die as a result of enhanced apoptosis. Instead, cell proliferation is impaired, and expression levels of cell cycle-associated proteins are altered. Individual cells survive, perhaps because cell survival mechanisms are activated. Thus, global compromise of ER and mitochondrial integrity caused by ceramide accumulation in CERT mutant mice primarily affects organogenesis rather than causing cell death via apoptotic pathways.
Wang
Xin
X
Laboratory of Cell and Developmental Signaling, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
Rao
Raghavendra Pralhada
RP
Kosakowska-Cholody
Teresa
T
Masood
M Athar
MA
Southon
Eileen
E
Zhang
Helin
H
Berthet
Cyril
C
Nagashim
Kunio
K
Veenstra
Timothy K
TK
Tessarollo
Lino
L
Acharya
Usha
U
Acharya
Jairaj K
JK
D000818:Animals; D017209:Apoptosis; D001692:Biological Transport / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D002518:Ceramides / Q000378:metabolism; D003433:Crosses, Genetic; D004622:Embryo, Mammalian / Q000166:cytology* / Q000378:metabolism / Q000648:ultrastructure; D047108:Embryonic Development / Q000235:genetics*; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000648:ultrastructure; D005838:Genotype; D006330:Heart Defects, Congenital / Q000196:embryology / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000235:genetics / Q000502:physiology* / Q000648:ultrastructure; D009154:Mutation; D038081:Organogenesis / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction
D002518:Ceramides; C535066:Col4a3bp protein, mouse; D017346:Protein Serine-Threonine Kinases