Keratin 8 protection of placental barrier function.
The intermediate filament protein keratin 8 (K8) is critical for the development of most mouse embryos beyond midgestation. We find that 68% of K8-/- embryos, in a sensitive genetic background, are rescued from placental bleeding and subsequent death by cellular complementation with wild-type tetraploid extraembryonic cells. This indicates that the primary defect responsible for K8-/- lethality is trophoblast giant cell layer failure. Furthermore, the genetic absence of maternal but not paternal TNF doubles the number of viable K8-/- embryos. Finally, we show that K8-/- concepti are more sensitive to a TNF-dependent epithelial apoptosis induced by the administration of concanavalin A (ConA) to pregnant mothers. The ConA-induced failure of the trophoblast giant cell barrier results in hematoma formation between the trophoblast giant cell layer and the embryonic yolk sac in a phenocopy of dying K8-deficient concepti in a sensitive genetic background. We conclude the lethality of K8-/- embryos is due to a TNF-sensitive failure of trophoblast giant cell barrier function. The keratin-dependent protection of trophoblast giant cells from a maternal TNF-dependent apoptotic challenge may be a key function of simple epithelial keratins.
Jaquemar
Daniel
D
The Burnham Institute, La Jolla, CA 92037, USA.
Kupriyanov
Sergey
S
Wankell
Miriam
M
Avis
Jacqueline
J
Benirschke
Kurt
K
Baribault
Hélène
H
Oshima
Robert G
RG
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D003208:Concanavalin A / Q000494:pharmacology; D005314:Embryonic and Fetal Development / Q000187:drug effects; D005260:Female; D017353:Gene Deletion; D015726:Giant Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006406:Hematoma / Q000378:metabolism / Q000473:pathology; D053533:Keratin-8; D007633:Keratins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010920:Placenta / Q000187:drug effects / Q000502:physiology*; D011247:Pregnancy; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II; D014327:Trophoblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015703:Antigens, CD; D053533:Keratin-8; C486595:Krt8 protein, mouse; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D007633:Keratins