C-terminal region of teneurin-1 co-localizes with the dystroglycan complex in adult mouse testes and regulates testicular size and testosterone production

Abstract

Testicular size is directly proportional to fertility potential and is dependent on the integration of developmental proteins, trophic factors, and sex steroids. The teneurins are transmembrane glycoproteins that function as signaling and cell adhesion molecules in the establishment and maintenance of the somatic gonad, gametogenesis, and basement membrane. Moreover, teneurins are thought to function redundantly to the extracellular matrix protein, dystroglycan. Encoded on the last exon of the teneurin genes is a family of bioactive peptides termed the teneurin C-terminal-associated peptides (TCAPs). One of these peptides, TCAP-1, functionally interacts with β-dystroglycan to act as a neuromodulatory peptide with trophic characteristics independent from the teneurins. However, little is known about the localization and relationship between the teneurin-TCAP-1 system and the dystroglycans in the gonad. In the adult mouse testis, immunoreactive TCAP-1 was localized to spermatogonia and spermatocytes and co-localized with β-dystroglycan. However, teneurin-1 was localized to the peritubular myoid cell layer of seminiferous tubules and tubules within the epididymis, and co-localized with α-dystroglycan and α-smooth muscle actin. TCAP-1-binding sites were identified in the germ cell layers and adluminal compartment of the seminiferous tubules, and epithelial cells of the epididymis. In vivo, TCAP-1 administration to adult mice for 9 days increased testicular size, seminiferous and epididymal tubule short-diameter and elevated testosterone levels. TCAP-1-treated mice also showed increased TCAP-1 immunoreactivity in the caput and corpa epididymis. Our data provide novel evidence of TCAP-1 localization in the testes that is distinct from teneurin-1, but is integrated through an association with the dystroglycan complex.

Characterization of the teneurin C-terminal associated peptide (TCAP) in the vase tunicate, Ciona intestinalis: A novel peptide system associated with energy metabolism and reproduction

“…5M-P). In these studies, however, a strong immunoreactive-TCAP signal on the plasma membrane in cell culture or at the basement membrane was not observed as previously established in mouse tissue (Chand et al, 2013a), because the epitope may have been obscured by the globular arrangement of the extracellular domain of the teneurins (Feng et al, 2002). Assuming this to be case, then we cannot discount the possibility that TCAP region of the C. intestinalis teneurin may act as a functional unit of teneurin by remaining tethered to it, in a similar manner to the notch signaling of serrate and delta ligands (Artavanis-Tsakonas et al, 1999;Hicks et al, 2002.…”

Ancient interaction between the teneurin C-terminal associated peptides (TCAP) and latrophilin ligand-receptor coupling: a role in behavior

“…These findings were partially resolved when TCAP-1 and teneurin-1 was investigated in the mouse testes. Here, the studies indicated a clear relationship of teneurin-1 with α-dystroglycan, and TCAP-1 with β-dystroglycan (Chand et al, 2014 ). However, in these studies, teneurin immunoreactivity was found at the cell membrane, whereas TCAP-1 immunoreactivity was typically found within the cytosol.…”

On the Teneurin track: a new synaptic organization molecule emerges

“…As all Teneurin homologs possess an NHL domain (Figure 1 ), which can interact with integrins (Löer et al, 2008 ), this suggests that such a mechanism could be conserved across species. In mice, there is further interplay between Teneurin and Dystroglycan, as the C-terminal region of Teneurin-1 colocalizes with Dystroglycan (Chand et al, 2012 , 2014 ). In hippocampal cultures, application of this C-terminus regulates cytoskeletal organization (presumably through Dystroglycan) by increasing tubulin levels, actin polymerization, and filopodia length and rate of formation.…”

“…Thus, Teneurin-1 is proposed to induce a signal beginning from Dystroglycan at the membrane and resulting in neurite elongation (Chand et al, 2012 ). In the testes, this interaction is conserved, as Teneurin-1 colocalizes with actin, regulating testosterone and testicular size (Chand et al, 2014 ). This conserved Teneurin-Dystroglycan interplay is thus poised to generally regulate the cytoskeleton.…”