Disruption of Spermatogenic Cell Adhesion and Male Infertility in Mice Lacking TSLC1/IGSF4, an Immunoglobulin Superfamily Cell Adhesion Molecule

TSLC1/IGSF4, an immunoglobulin superfamily molecule, is predominantly expressed in the brain, lungs, and testes and plays important roles in epithelial cell adhesion, cancer invasion, and synapse formation. We generated Tslc1/Igsf4-deficient mice by disrupting exon 1 of the gene and found that Tslc1 / mice were born with the expected Mendelian ratio but that Tslc1 / male mice were infertile. In 11-week-old adult Tslc1 / mice, the weight of a testis was 88% that in Tslc1 / mice, and the number of sperm in the semen was approximately 0.01% that in Tslc1 / mice. Histological analysis revealed that the round spermatids and the pachytene spermatocytes failed to attach to the Sertoli cells in the seminiferous tubules and sloughed off into the lumen with apoptosis in the Tslc1 / mice. On the other hand, the spermatogonia and the interstitial cells, including Leydig cells, were essentially unaffected. In the Tslc1 / mice, TSLC1/IGSF4 expression was observed in the spermatogenic cells from the intermediate spermatogonia to the early pachytene spermatocytes and from spermatids at step 7 or later. These findings suggest that TSLC1/IGSF4 expression is indispensable for the adhesion of spermatocytes and spermatids to Sertoli cells and for their normal differentiation into mature spermatozoa. Infertility is estimated to affect about 5% of adult human males. However, approximately 75% of these cases are diagnosed as idiopathic because the molecular mechanisms underlying these defects have not been elucidated (17, 20). Recently, male infertility has been reported as a phenotype in mice that are deficient in various single genes, providing knowledge about possible molecular targets causing male infertility in humans. So far, more than 80 genes have been identified as essential for male fertility in humans and mice (11). These genes encode a variety of proteins, including signal transduction molecules, transcription factors, metabolic enzymes, transmembrane proteins, and cytoskeletal proteins. From the pathological point of view, the causes of male infertility can be grouped into the following three categories, depending on the stage of cell differentiation affected: defects in the primordial germ cells, those in the spermatogenic cells, and those in the spermatozoa. Among these defects, abnormalities in the genes involved in the primordial germ cells and the resultant developmental defects in the reproductive organs are relatively rare, probably because such defects often cause embryonic lethality. On the other hand, spermatogenesis, a series of spermatogenic cell differentiation steps from spermatogonia to mature spermatozoa in the testes, is considered the major target of defects in male infertility. In fact, about 70% of the genes essential for male fertility are involved in this process. Another 20% of the genes have been shown to play a role in the formation, motility,