The cell adhesion molecule BT-IgSF is essential for a functional blood–testis barrier and male fertility in mice

Abstract

The Ig-like cell adhesion molecule (IgCAM) BT-IgSF (brain- and testis-specific Ig superfamily protein) plays a major role in male fertility in mice. However, the molecular mechanism by which BT-IgSF supports fertility is unclear. Here, we found that it is localized in Sertoli cells at the blood-testis barrier (BTB) and at the apical ectoplasmic specialization. The absence of BT-IgSF in Sertoli cells in both global and conditional mouse mutants ( AMHCre and Rosa26CreERT2 lines) resulted in male infertility, atrophic testes with vacuolation, azoospermia, and spermatogenesis arrest. Although transcripts of junctional proteins such as connexin43, ZO-1, occludin, and claudin11 were up-regulated in the absence of BT-IgSF, the functional integrity of the BTB was impaired, as revealed by injection of a BTB-impermeable component into the testes under conditions. Disruption of the BTB coincided with mislocalization of connexin43, which was present throughout the seminiferous epithelium and not restricted to the BTB as in wild-type tissues, suggesting impaired cell-cell communication in the BT-IgSF-KO mice. Because EM images revealed a normal BTB structure between Sertoli cells in the BT-IgSF-KO mice, we conclude that infertility in these mice is most likely caused by a functionally impaired BTB. In summary, our results indicate that BT-IgSF is expressed at the BTB and is required for male fertility by supporting the functional integrity of the BTB.

The IgCAM CLMP regulates expression of Connexin43 and Connexin45 in intestinal and ureteral smooth muscle contraction in mice

“…Formation of a molecular complex between CLMP and ZO-1 and Connexin43 or Connexin45 is therefore conceivable. Our studies are in part in line with observations on the related IgCAMs CAR and BT-IgSF, which might be implicated in the regulation of Connexin45 or Connexin43 in cardiomyocytes or Sertoli cells, respectively ( Lisewski et al, 2008 ; Lim et al, 2008 ; Pelz et al, 2017 ). Furthermore, whether CLMP exerts its function on Connexin43 or 45 also in other cell types such as neurons or smooth muscle cells of the cardiovascular system would be an essential topic of future research.…”

IgSF11 regulates osteoclast differentiation through association with the scaffold protein PSD-95

“…S2d). Similar to previous reports, male IgSF11 −/− mice were found to exhibit smaller testis and infertility, 19 albeit with no apparent differences in body weight or size observed between IgSF11 +/+ and IgSF11 −/− mice ( Fig. S2e and data not shown).…”

“…S2e and data not shown). No generative dysfunction was observed in IgSF11 +/− males or IgSF11 −/− females 19 (data not shown).…”

“…18 In the testis, IgSF11 has been demonstrated to be expressed in Sertoli cells and to maintain a functional blood-testis barrier. 19 Recently, IgSF11 has been identified as a ligand of the B7 family member V-domain Ig suppressor of T-cell activation (VISTA, also known as PD-1H), 20 which has been revealed to have inhibitory effects on human T cell function. 21 IgSF11 has also been characterized as a gene frequently upregulated in intestinal type gastric cancers.…”

The CAR group of Ig cell adhesion proteins–Regulators of gap junctions?

“…However, electron microscopy images did not reveal any changes in the ultrastructure of the blood‐testes barrier in the absence of BT‐IgSF, but instead a mislocalization of connexin43 was detected. Connexin43 was found throughout the seminiferous epithelium and instead of being restricted to the blood‐testes barrier as it is in wild type tissues [ 47 ] (Figure 4a). Connexin43 is known to play an essential role in tight junction reassembly at the blood‐testes barrier during its restructuring processes.…”