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Vol. 19, Issue 6, 2465-2475, June 2008

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Deficiency of Zonula Occludens-1 Causes Embryonic Lethal Phenotype Associated with Defected Yolk Sac Angiogenesis and Apoptosis of Embryonic Cells

Tatsuya Katsuno^*,, Kazuaki Umeda^,,||, Takeshi Matsui^*,¶, Masaki Hata^,#, Atsushi Tamura^*, Masahiko Itoh^,@, Kosei Takeuchi^,**, Toshihiko Fujimori, Yo-ichi Nabeshima, Tetsuo Noda, Shoichiro Tsukita, and Sachiko Tsukita^*

*Laboratory of Biological Science, Graduate School of Frontier Biosciences, and Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; Department of Biological Science, Nagoya University Graduate School of Science, Nagoya 464-8602, Japan; Department of Cell Biology, Faculty of Medicine, Kyoto University, Kyoto 606-8501, Japan; KAN Research Institute, Inc., Kobe MI R&D Center, Kobe 650-0047, Japan; Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan; and Department of Cell Biology, Cancer Institute of the Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan

Submitted December 6, 2007; Revised February 25, 2008; Accepted March 10, 2008
Monitoring Editor: Keith Mostov

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.

Present addresses: ^|| Department of Molecular Pharmacology, Graduate School of Medical Science, Kumamoto University, Honjo, Kumamoto 860-8556, Japan;

^¶ Medical Top Track Program, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 135-8550, Japan;

^# Department of Pathology, Hyogo College of Medicine, 4-11 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan;

^@ Department of Molecular and Cell Biology, Institute of Medical Science, Dokkyo Medical University, Shimotsuga-gun, Tochigi, 321-0293 Japan;

** Department of Anatomy and Developmental Biology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.

Address correspondence to: Sachiko Tsukita (atsukita{at}biosci.med.osaka-u.ac.jp).

Abbreviations used: MAGUK, membrane-associated guanylate kinase; TJ, tight junction; AJ, adherens junction; PDZ, postsynaptic density 95/disc-large/zona occludens; ZA, zonula adherens; ZO, zonula occludens.