Deficiency of zonula occludens-1 causes embryonic lethal phenotype associated with defected yolk sac angiogenesis and apoptosis of embryonic cells.
Zonula occludens (ZO)-1/2/3 are the members of the TJ-MAGUK family of membrane-associated guanylate kinases associated with tight junctions. To investigate the role of ZO-1 (encoded by Tjp1) in vivo, ZO-1 knockout (Tjp1(-/-)) mice were generated by gene targeting. Although heterozygous mice showed normal development and fertility, delayed growth and development were evident from E8.5 onward in Tjp1(-/-) embryos, and no viable Tjp1(-/-) embryos were observed beyond E11.5. Tjp1(-/-) embryos exhibited massive apoptosis in the notochord, neural tube area, and allantois at embryonic day (E)9.5. In the yolk sac, the ZO-1 deficiency induced defects in vascular development, with impaired formation of vascular trees, along with defective chorioallantoic fusion. Immunostaining of wild-type embryos at E8.5 for ZO-1/2/3 revealed that ZO-1/2 were expressed in almost all embryonic cells, showing tight junction-localizing patterns, with or without ZO-3, which was confined to the epithelial cells. ZO-1 deficiency depleted ZO-1-expression without influence on ZO-2/3 expression. In Tjp1(+/+) yolk sac extraembryonic mesoderm, ZO-1 was dominant without ZO-2/3 expression. Thus, ZO-1 deficiency resulted in mesoderms with no ZO-1/2/3, associated with mislocalization of endothelial junctional adhesion molecules. As a result, angiogenesis was defected in Tjp1(-/-) yolk sac, although differentiation of endothelial cells seemed to be normal. In conclusion, ZO-1 may be functionally important for cell remodeling and tissue organization in both the embryonic and extraembryonic regions, thus playing an essential role in embryonic development.
Katsuno
Tatsuya
T
Laboratory of Biological Science, Graduate School of Frontier Biosciences, and Graduate School of Medicine, Osaka University, Japan.
Umeda
Kazuaki
K
Matsui
Takeshi
T
Hata
Masaki
M
Tamura
Atsushi
A
Itoh
Masahiko
M
Takeuchi
Kosei
K
Fujimori
Toshihiko
T
Nabeshima
Yo-ichi
Y
Noda
Tetsuo
T
Tsukita
Shoichiro
S
Tsukita
Sachiko
S
D000818:Animals; D017209:Apoptosis; D001681:Biological Assay; D002352:Carrier Proteins / Q000378:metabolism; D020964:Embryo Loss / Q000378:metabolism* / Q000473:pathology*; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000473:pathology*; D047108:Embryonic Development; D004707:Endoderm / Q000166:cytology / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006720:Homozygote; D008565:Membrane Proteins / Q000172:deficiency* / Q000378:metabolism; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000196:embryology*; D010641:Phenotype; D010750:Phosphoproteins / Q000172:deficiency* / Q000378:metabolism; D015017:Yolk Sac / Q000098:blood supply* / Q000473:pathology; D062825:Zonula Occludens Proteins; D062826:Zonula Occludens-1 Protein; D062827:Zonula Occludens-2 Protein
D002352:Carrier Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; C569043:Tjp1 protein, mouse; C569047:Tjp2 protein, mouse; C491774:Tjp3 protein, mouse; D062825:Zonula Occludens Proteins; D062826:Zonula Occludens-1 Protein; D062827:Zonula Occludens-2 Protein