Claudin-11 is over-expressed and dislocated from the blood–testis barrier in Sertoli cells associated with testicular intraepithelial neoplasia in men

Abstract

In mouse testis, claudin-11 is responsible for the formation of specific parallel TJ strands of the blood-testis barrier (BTB). Concerning the human BTB, there is no information about the transmembrane TJ proteins. We recently demonstrated the loss of functional integrity of the BTB in testicular intraepithelial neoplasia (TIN), associated with a dislocation of the peripheral TJ proteins ZO-1 and ZO-2. Here, we determined the expression and distribution of claudin-11 at the human BTB in seminiferous tubules with normal spermatogenesis (NSP) and TIN. Immunostaining of claudin-11 revealed intense signals at the basal BTB region in seminiferous epithelium with NSP. Within TIN tubules, claudin-11 immunostaining became diffuse and cytoplasmic. Double immunogold labeling demonstrated a co-localization of claudin-11 and ZO-1 at the inter-Sertoli cell junctions. Real-time RT-PCR of laser microdissected tubules showed an up-regulation of claudin-11 mRNA in TIN. Additionally, increased claudin-11 protein was observed by Western blot. We conclude that claudin-11 constitutes a TJ protein at the human BTB. In TIN tubules, claudin-11 is up-regulated and dislocated from the BTB. Therefore, the disruption of the BTB is related to a dysfunction of claudin-11 and not to a failure of its expression.

Blood–testis barrier and Sertoli cell function: lessons from SCCx43KO mice

“…Also in men, impaired spermatogenesis can be associated with an altered BTB composition and function (Cavicchia et al 1996). In men with testicular carcinoma-in-situ (CIS), CLAUDIN11 has been found to be overexpressed in SC (Fink et al 2009), associated with a downregulation of CX43 (Brehm et al 2002(Brehm et al , 2006. In addition, CLAUDIN11 and CX43 were found to have altered spatial patterns of organization in men with primary seminiferous tubule failures (meiotic arrest and SC-only syndrome (SCO); Haverfield et al 2013).…”

“…With w1/3 of infertile men are being diagnosed with idiopathic infertility (Schatzl & Schmidbauer 2009). In this context, the SCCx43KO mouse model might supply background information or mechanistic insights into unknown causes for human male infertility as it has been shown in different studies that CX43 is downregulated in men associated with different histological phenotypes of spermatogenic impairment (Steger et al 1999, Brehm et al 2002 and associated with BTBalterations (Fink et al 2009, Haverfield et al 2013.…”

Claudin and occludin expression and function in the seminiferous epithelium

“…Compared with the expression in tubules with normal spermatogenesis, claudin 11 mRNA and protein are both increased in tubules with TIN (Fink et al 2009). However, claudin 11 protein localization in tubules with TIN is substantially decreased at the BTB and increased in the cytoplasm (Fink et al 2009).…”

Claudins and germ cell tumors

“…In studies on claudin 11 expression in these lesions, claudin 11 expression was increased but the increased did not take place in the neoplastic germ cells but in Sertoli cells where claudin 11 was displaced from the membrane (45). The relative protein expression of claudins 1-7 in testicular germ cell neoplasia and testicular tissue is presented in …”

“…Claudin 11 is present in Sertoli cells and takes part in formation of the blood testis barrier (44). In normal seminiferous epithelium claudin 11 is located at the basal compartment and the distribution is similar to ZO1 and ZO2 in this location (45). Claudin 1, 3 and 11 expression in Sertoli cells of mouse and rat testis appears to be regulated by androgens (46,47,48).…”