Retinoid X receptor beta (RXRB) expression in Sertoli cells controls cholesterol homeostasis and spermiation

Abstract

Somatic, targeted inactivation of the retinoid X receptor beta gene (Rxrb) in Sertoli cells (SC; yielding Rxrb SerK/K mutants) leads to failure of spermatid release, accumulation of cholesterol esters and, subsequently, testis degeneration. These abnormalities are identical, in their nature and kinetics, to those observed upon inactivating Rxrb in the whole organism, thereby demonstrating that all reproductive functions of RXRB are carried out in SC. The Rxrb SerK/K testis degeneration is a consequence of a cholesterol ester cell overload occurring in SC in response to reduced ABCA1-and SCARB1-mediated cholesterol efflux. The failure of spermiation was also reported in mice lacking the retinoic acid (RA) receptor-a (RARA) in SC (Rara SerK/K mutants) and represents, in addition, a feature of vitamin A deficiency that can be readily induced in mice lacking the lecithin:retinol acyltransferase (Lrat K/K mutants). Altogether, these findings support the conclusion that RXRB heterodimerized with a RA-liganded RARA transduces signals required in SC for spermatid release.

Spermiation

“…RARα is activated by RA but ligand-dependent activation of RXRβ is not required for spermiation. 82,84 Spermiation failure is an acute feature of and is highly sensitive to, a lack of RA signaling and is manifested by retained spermatids in stages IX-X and a reduced epididymal sperm count. Some spermatids fail to initiate spermiation in stage VII 83,84 whereas others may fail to disengage.…”

“…82,84 Spermiation failure is an acute feature of and is highly sensitive to, a lack of RA signaling and is manifested by retained spermatids in stages IX-X and a reduced epididymal sperm count. Some spermatids fail to initiate spermiation in stage VII 83,84 whereas others may fail to disengage. RARα/RXRβ in Sertoli cells may co-operate to some degree with AR signaling and/or regulate the expression of adhesion junction components (reviewed in ref.…”

“…RARα/RXRβ in Sertoli cells may co-operate to some degree with AR signaling and/or regulate the expression of adhesion junction components (reviewed in ref. 84 and references therein).…”

Metabolic Cooperation in Testis as a Pharmacological Target: From Disease to Contraception

“…Notably, the testis are enriched in several metaboliz-ing enzymes of vitamin A [184]. Besides the possible relevance of these enzymes [185], it has also been highlighted that signaling proteins involved in these processes are also possible relevant targets to develop a male contraceptive [186][187][188][189]. Nevertheless, research is still needed to disclose retinoic acid role on germ cells development, as well as its metabolism in testis and how can drugs specifically target testicular retinoic acid metabolism.…”

Surfing the wave, cycle, life history, and genes/proteins expressed by testicular germ cells. Part 5: Intercellular junctions and contacts between germs cells and Sertoli cells and their regulatory interactions, testicular cholesterol, and genes/proteins associated with more than one germ cell generation

“…Targeted inactivation of Rxrb specifically in Sertoli cells results in cholesterol ester accumulation in these cells because of reduced ABCA1 [ID: T4-725]-and SCARB1 [ID: T5-941]-mediated cholesterol efflux. There is failure of spermatids to undergo spermiation leading to degeneration of the testis (Vernet et al, 2008).…”