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

Abstract

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 Tslc1mice, 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.

In vivo differentiation and genomic evolution in adult male germ cell tumors

“…While targeted disruption of IGSF4 (TSLC1) on 11q23.2 has previ- ously been shown to lead to infertility in mice, suggesting an important role in spermatogenesis (Yamada et al, 2006), it has also been shown to be a tumor suppressor gene in both lung (Kuramochi et al, 2001) and ovarian cancer (Ehrlich et al, 2006). Interestingly, one of the other tumor suppressor genes that we identified, EPB41L3 on chromosome 18, is a known partner of TSLC1.…”

Six cadm/synCAM genes are expressed in the nervous system of developing zebrafish

“…The Cadms (cell adhesion molecules) are a family of type I transmembrane proteins that have been described in several pathological and physiological processes such as the progression of lung and other cancers (reviewed in Murakami, 2005), mast cell adhesion (Ito et al, 2003(Ito et al, , 2007bFuruno et al, 2005;Ito and Oonuma, 2006), spermatogenesis (Wakayama et al, 2001;Wakayama et al, 2003;Fujita et al, 2006;van der Weyden et al, 2006;Yamada et al, 2006), epithelium development and homeostasis (Ito et al, 2007b), and central nervous system development (Biederer et al, 2002;Sara et al, 2005;Spiegel et al, 2007).…”

“…Infertility is probably caused by a delay in the maturation of sperm cells, leading to an increase in apoptosis. The deficit in sperm cell maturation is due to an alteration of the adhesion between spermatogenic cells and the Sertoli cells Fujita et al, 2006;van der Weyden et al, 2006;Yamada et al, 2006).…”

Cell adhesion molecule 1: a novel risk factor for venous thrombosis

“…37,38 Decreased expression of CADM1 has been associated with nonsmall cell lung cancer, 40 other solid tumors, [41][42][43][44] and with infertility in homozygous deficient transgenic mice. 39 Interestingly, ectopic expression of CADM1 has been associated with adult T-cell leukemia with the suggestion that it mediates binding of tumor cells to endothelium, thus facilitating tumor invasion. 45,46 A search of the literature failed to identify an evaluation for the presence of CADM1 in endothelial cells other than 2 articles, where it was not observed using immunohistochemistry in the pulmonary vasculature.…”

“…30,[35][36][37][38] CADM1 plays a variety of different roles in cell-cell adhesion. Examples of the disparate functions of CADM1 include basolateral adhesion of pulmonary epithelial cells, 30 organization of synapse formation, 35 adhesion of spermatogonia to Sertoli cells, 39 and adhesion of mast cells to nerve and smooth muscle cells. 37,38 Decreased expression of CADM1 has been associated with nonsmall cell lung cancer, 40 other solid tumors, [41][42][43][44] and with infertility in homozygous deficient transgenic mice.…”