Dataset Information

SOX8 regulates permeability of the blood-testes barrier that affects adult male fertility in the mouse.

ABSTRACT: Sertoli cells provide nutritional and physical support to germ cells during spermatogenesis. Sox8 encodes a member of the high mobility group of transcription factors closely related to Sox9 and Sox10. Sertoli cells express SOX8 protein, and its elimination results in an age-dependent dysregulation of spermatogenesis, causing adult male infertility. Among the claudin genes with altered expression in the Sox8(-/-) testes, was claudin-3, which is required for the regulation and maintenance of the blood-testes barrier (BTB). Because the BTB is critical in restricting small molecules in the luminal compartment of the seminiferous tubules, the aim of this study was to analyze the level of tight junction proteins (claudin-3, claudin-11, and occludin) and BTB permeability in Sox8(-/-) adult testes. The acetylation level of alpha-tubulin and microtubule organization was also evaluated because microtubules are critical in maintaining the microenvironment of the seminiferous epithelium. Western blot analysis shows that claudin-3 protein is decreased in Sox8(-/-) testes. Chromatin immunoprecipitation confirmed that SOX8 binds at the promoter region of claudin-3. Claudin-3 was localized to the Sertoli cell tight junctions of wild-type testes and significantly decreased in the Sox8(-/-) testes. The use of biotin tracers showed increased BTB permeability in the Sox8(-/-) adult testes. Electron microscopy analysis showed that microtubule structures were destabilized in the Sox8(-/-) testes. These results suggest that Sox8 is essential in Sertoli cells for germ cell differentiation, partly by controlling the microenvironment of the seminiferous epithelium.

SUBMITTER: Singh AP

PROVIDER: S-EPMC4434911 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Serum leptin levels are augmented in obese infertile men and in men with azoospermia. They also correlate inversely with sperm concentration, motility and normal forms. The mechanisms underlying the adverse effects of excess leptin on male reproductive function remain unclear. The present study aimed to evaluate the effects of exogenous leptin on sperm parameters in mice and to explore the underlying mechanisms.We treated normal adult male mice with saline, 0.1, 0.5 or 3 mg/kg leptin daily for 2 weeks. After treatment, serum leptin levels, serum testosterone levels, sperm parameters and testicular cell apoptosis were evaluated. Blood testis barrier integrity and the expression of tight junction-associated proteins in testes were also assessed. We further verified the direct effects of leptin on tight junction-associated proteins in Sertoli cells and the possible leptin signaling pathways involved in this process.After treatment, there were no significant differences in body weights, reproductive organ weights, serum leptin levels and serum testosterone levels between leptin-treated mice and control mice. Administration of 3 mg/kg leptin reduced sperm concentration, motility and progressive motility while increasing the percentage of abnormal sperm and testicular cell apoptosis. Mice treated with 3 mg/kg leptin also had impaired blood testis barrier integrity, which was related to decreased tight junction-associated proteins in testes. Leptin directly reduced tight junction-associated proteins in Sertoli cells, JAK2/STAT, PI3K and ERK pathways were suggested to be involved in this process.Exogenous leptin negatively affects sperm parameters and impairs blood testis barrier integrity in mice. Leptin reduced tight junction-associated proteins in Sertoli cells, indicating that leptin has a direct role in impairing blood testis barrier integrity. Given the function of blood testis barrier in maintaining normal spermatogenesis, leptin-induced blood testis barrier impairment may be one of the mechanisms contributing to male subfertility and infertility.

Project description:BACKGROUND:Acute neurological insults caused by infection, systemic inflammation, ischemia, or traumatic injury are often associated with breakdown of the blood-brain barrier (BBB) followed by infiltration of peripheral immune cells, cytotoxic proteins, and water. BBB breakdown and extravasation of these peripheral components into the brain parenchyma result in inflammation, oxidative stress, edema, excitotoxicity, and neurodegeneration. These downstream consequences of BBB dysfunction can drive pathophysiological processes and play a substantial role in the morbidity and mortality of acute and chronic neurological insults, and contribute to long-term sequelae. Preserving or rescuing BBB integrity and homeostasis therefore represents a translational research area of high therapeutic potential. METHODS:Induction of general and localized BBB disruption in mice was carried out using systemic administration of LPS and focal photothrombotic ischemic insult, respectively, in the presence and absence of the monoacylglycerol lipase (MAGL) inhibitor, CPD-4645. The effects of CPD-4645 treatment were assessed by gene expression analysis performed on neurovascular-enriched brain fractions, cytokine and inflammatory mediator measurement, and functional assessment of BBB permeability. The mechanism of action of CPD-4645 was studied pharmacologically using inverse agonists/antagonists of the cannabinoid receptors CB1 and CB2. RESULTS:Here, we demonstrate that the neurovasculature exhibits a unique transcriptional signature following inflammatory insults, and pharmacological inhibition of MAGL using a newly characterized inhibitor rescues the transcriptional profile of brain vasculature and restores its functional homeostasis. This pronounced effect of MAGL inhibition on blood-brain barrier permeability is evident following both systemic inflammatory and localized ischemic insults. Mechanistically, the protective effects of the MAGL inhibitor are partially mediated by cannabinoid receptor signaling in the ischemic brain insult. CONCLUSIONS:Our results support considering MAGL inhibitors as potential therapeutics for BBB dysfunction and cerebral edema associated with inflammatory brain insults.

Dataset Information

SOX8 regulates permeability of the blood-testes barrier that affects adult male fertility in the mouse.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets