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During spermatogenesis, cell-cell actin-based adherens junctions (AJ), such as ectoplasmic specializations (ES), between Sertoli and germ cells undergo extensive restructuring in the seminiferous epithelium to facilitate germ cell movement across the epithelium. While the mechanism(s) that regulates AJ dynamics in the testis is virtually unknown, Rho GTPases have been implicated in the regulation of these events in other epithelia. Studies reported herein have shown that the in vitro assembly of the Sertoli-germ cell AJs, but not the Sertoli cell tight junctions (TJs), indeed associated with a transient but significant induction of RhoB. Studies by immunohistochemistry have shown that the localization of RhoB in the seminiferous epithelium was stage-specific, being lowest in stages VII-VIII prior to spermiation, and displayed cell specific association during the epithelial cycle. Throughout the cycle, RhoB was localized near the site of basal and apical ES, but restricted to the periphery of the nuclei in elongating (but not elongated) spermatids, spermatocytes and Sertoli cells. Yet RhoB was not detected near the site of apical ES at stages VII-VIII. Furthermore, disruption of AJs in Sertoli-germ cell cocultures either by hypotonic treatment or by treatment with 1-(2,4-dichlorobenzyl)-indazole-3-carbohydrazide (AF-2364) also induced RhoB expression. When adult rats were treated with AF-2364 to perturb Sertoli-germ cell AJs in vivo, a ~4-fold induction in RhoB in the testis, but not in kidney and brain, was detected within 1 hr, which was at least ~1-4 days before germ cell loss from the epithelium could be detected by histological analysis. The signaling pathway(s) by which AF-2364 perturbed the Sertoli-germ cell AJs apparently began with an initial activation of integrin. This in turn activated RhoB, ROCK1, LIMK1 and cofilin, but not p140mDia and profilin via phosphorylation. Immunoprecipitation and immunoblots revealed that the induction of LIMK1 was mediated via an increase in its phospho-Ser, but not phospho-Tyr, content. Furthermore, Y-27632, a specific ROCK inhibitor, could effectively delay the AF-2364-induced germ cell loss from the seminiferous epithelium in vivo, illustrating the integrin/RhoB/ROCK/LIMK pathway indeed plays a crucial role in the regulation of Sertoli-germ cell AJ dynamics. The fact that the RhoB pathway in the kidney and brain was not activated suggests that AF-2364 exerts its effects primarily at the testis-specific ES multi-protein complex structures between Sertoli cells and spermatids.
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