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The Population Council (M.K.Y.S., D.D.M., C.Y.C.), Center for Biomedical Research, New York, New York 10021; and Department of Zoology (W.M.L.), University of Hong Kong, Hong Kong, Special Administrative Region of China
Address all correspondence and requests for reprints to: C. Yan Cheng, Ph.D., The Population Council, 1230 York Avenue, New York, New York 10021. E-mail: y-cheng{at}popcbr.rockefeller.edu.
During spermatogenesis, the movement of developing germ cells across the seminiferous epithelium associates with extensive restructuring of cell-cell actin-based adherens junctions (AJs), such as ectoplasmic specialization (ES, a testis-specific AJ junction), between Sertoli and germ cells. Although this event of germ cell movement is essential to the completion of spermatogenesis, the mechanism(s) that regulates AJ restructuring is largely unknown. Using Sertoli-germ cells cocultured in vitro to study the regulation of AJ assembly, it was shown that this event associated with a transient induction of ß1-integrin, vinculin, p-FAK-Tyr397, and phosphatidylinositol 3-kinase (PI3K) but not the nonphosphorylated form of focal adhesion kinase (FAK), paxillin, and p130 Cas. Furthermore, p-FAK-Tyr397 was shown to coimmunoprecipitate with ß1-integrin, vinculin, and c-Src both in vitro and in vivo using Sertoli-germ cell cocultures and seminiferous tubules, respectively. These results seemingly suggest that the testis is using constituent proteins of the focal adhesion complex (FAC) found in other epithelia between cell and extracellular matrix to regulate AJ dynamics. To further confirm that p-FAK, a putative FAC protein in other epithelia, is indeed present at the site of ES, immunohistochemistry and immunofluorescent microscopy were used. The p-FAK-Tyr397 and p-FAK-Tyr576 were found to localize almost exclusively at the site of apical ES with weak staining at the basal ES in the seminiferous epithelium in a stage-specific manner, being highest at stages VI–VIII. In contrast, FAK was largely restricted to the basal compartment but with weak staining at the apical compartment. When rats were treated with 1-(2,4-dichlorobenzyl)-indazole-3-carbohydrazide (AF-2364) to perturb Sertoli-germ cell AJs, an induction of ß1-integrin, vinculin, p-FAK-Tyr397, PI3K, and p130 Cas but not the nonphosphorylated form of FAK and paxillin was also detected in the testis, coinciding with the time spermatids began to deplete from the epithelium, indicating their involvement in AJ disassembly. Thereafter, the levels of vinculin, p-FAK-Tyr397, PI3K, and p130 Cas in the testis plunged, coinciding with the declining events of AJ disruption when virtually all spermatids were depleted from the epithelium. Taken collectively, these results suggest a bifunctional role of p-FAK, being involved in the events of Sertoli-germ cell AJ assembly and disassembly. In summary, the events of AJ dynamics in the testis, in particular at the site of ES, are regulated, at least in part, by proteins that are found in the FAC in other epithelia, such as ß1-integrin, vinculin, and FAK utilizing the integrin/pFAK/PI3K/p130 Cas signaling pathway.
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