Zona Occludens-2 Is Critical for Blood–Testis Barrier Integrity and Male Fertility |
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Authors: | Jianliang Xu Farhana Anuar Safiah Mohamed Ali Mei Yong Ng Dominic CY Phua Walter Hunziker |
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Institution: | Epithelial Cell Biology Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 138673 |
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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 chimera 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. |
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