Deficiency of zonula occludens-1 causes embryonic lethal phenotype associated with defected yolk sac angiogenesis and apoptosis of embryonic cells

Mol Biol Cell. 2008 Jun;19(6):2465-75. doi: 10.1091/mbc.e07-12-1215. Epub 2008 Mar 19.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Biological Assay
  • Carrier Proteins / metabolism
  • Embryo Loss / metabolism*
  • Embryo Loss / pathology*
  • Embryo, Mammalian / abnormalities
  • Embryo, Mammalian / pathology*
  • Embryonic Development
  • Endoderm / cytology
  • Endoderm / metabolism
  • Fluorescent Antibody Technique
  • Homozygote
  • Membrane Proteins / deficiency*
  • Membrane Proteins / metabolism
  • Mesoderm / cytology
  • Mesoderm / metabolism
  • Mice
  • Mice, Knockout
  • Mutation / genetics
  • Neovascularization, Pathologic / embryology*
  • Phenotype
  • Phosphoproteins / deficiency*
  • Phosphoproteins / metabolism
  • Yolk Sac / blood supply*
  • Yolk Sac / pathology
  • Zonula Occludens Proteins
  • Zonula Occludens-1 Protein
  • Zonula Occludens-2 Protein

Substances

  • Carrier Proteins
  • Membrane Proteins
  • Phosphoproteins
  • Tjp1 protein, mouse
  • Tjp2 protein, mouse
  • Tjp3 protein, mouse
  • Zonula Occludens Proteins
  • Zonula Occludens-1 Protein
  • Zonula Occludens-2 Protein