title: Zona occludens-2 is critical for blood-testis barrier integrity and male fertility.
abstract: Tight junction integral membrane proteins such as claudins and occludin are tethered to the actin cytoskeleton by adaptor proteins, notably the closely related zonula occludens (ZO) proteins ZO-1, ZO-2, and ZO-3. All three ZO proteins have recently been inactivated in mice. Although ZO-3 knockout mice lack an obvious phenotype, animals deficient in ZO-1 or ZO-2 show early embryonic lethality. Here, we rescue the embryonic lethality of ZO-2 knockout mice by injecting ZO-2(-/-) embryonic stem (ES) cells into wild-type blastocysts to generate viable ZO-2 chimera. ZO-2(-/-) ES cells contribute extensively to different tissues of the chimera, consistent with an extraembryonic requirement for ZO-2 rather than a critical role in epiblast development. Adult chimera present a set of phenotypes in different organs. In particular, male ZO-2 chimeras show reduced fertility and pathological changes in the testis. Lanthanum tracer experiments show a compromised blood-testis barrier. Expression levels of ZO-1, ZO-3, claudin-11, and occludin are not apparently affected. ZO-1 and occludin still localize to the blood-testis barrier region, but claudin-11 is less well restricted and the localization of connexin-43 is perturbed. The critical role of ZO-2 for male fertility and blood-testis barrier integrity thus provides a first example for a nonredundant role of an individual ZO protein in adult mice.
authors.affiliation: Epithelial Cell Biology Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 138673.
authors.forename: Jianliang
authors.initials: J
authors.lastname: Xu
authors.forename: Farhana
authors.initials: F
authors.lastname: Anuar
authors.forename: Safiah Mohamed
authors.initials: SM
authors.lastname: Ali
authors.forename: Mei Yong
authors.initials: MY
authors.lastname: Ng
authors.forename: Dominic C Y
authors.initials: DC
authors.lastname: Phua
authors.forename: Walter
authors.initials: W
authors.lastname: Hunziker
mesh_terms: D000818:Animals; D001814:Blood-Testis Barrier / Q000502:physiology*; D002678:Chimera; D057167:Claudins; D018031:Connexin 43 / Q000032:analysis; D005260:Female; D055786:Gene Knockout Techniques; D007248:Infertility, Male / Q000235:genetics* / Q000473:pathology; D007811:Lanthanum / Q000493:pharmacokinetics; D008297:Male; D008565:Membrane Proteins / Q000032:analysis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000032:analysis; D062793:Occludin; D010641:Phenotype; D010750:Phosphoproteins / Q000032:analysis; D012708:Sertoli Cells / Q000737:chemistry / Q000473:pathology*; D019108:Tight Junctions / Q000737:chemistry / Q000473:pathology*; D062826:Zonula Occludens-1 Protein; D062827:Zonula Occludens-2 Protein
chemical_list: D057167:Claudins; C492354:Cldn11 protein, mouse; D018031:Connexin 43; C543076:GJA1 protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D062793:Occludin; C568986:Ocln protein, mouse; D010750:Phosphoproteins; C569043:Tjp1 protein, mouse; C569047:Tjp2 protein, mouse; D062826:Zonula Occludens-1 Protein; D062827:Zonula Occludens-2 Protein; C016534:lanthanide nitrate; D007811:Lanthanum
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