RESUMEN
beta-TrCP, the substrate recognition subunit of a Skp1-Cul1-F-box (SCF) ubiquitin ligase, is ubiquitously expressed from two distinct paralogs, targeting many regulatory proteins for proteasomal degradation. We generated inducible beta-TrCP hypomorphic mice and found that they are surprisingly healthy, yet have a severe testicular defect. We show that the two beta-TrCP paralogs have a nonredundant role in spermatogenesis. The testicular defect is tightly associated with cell adhesion failure within the seminiferous tubules and is fully reversible upon beta-TrCP restoration. Remarkably, testicular depletion of a single beta-TrCP substrate, Snail1, rescued the adhesion defect and restored spermatogenesis. Our studies highlight an unexpected functional reserve of this central E3, as well as a bottleneck in a specific tissue: a single substrate whose stabilization is incompatible with testicular differentiation.
Asunto(s)
Proteínas Ligasas SKP Cullina F-box/genética , Proteínas Ligasas SKP Cullina F-box/metabolismo , Espermatogénesis/fisiología , Testículo/embriología , Factores de Transcripción/deficiencia , Animales , Uniones Intercelulares/patología , Masculino , Ratones , Ratones Transgénicos , Modelos Animales , Fenotipo , Isoformas de Proteínas , Factores de Transcripción de la Familia Snail , Testículo/patología , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
AIM: To determine the effect of nonylphenol-ethoxylate-10 (NP-10) on the ovarian reserve in a mouse model. DESIGN: Female mice were maintained on purified water or exposed to NP-10 from 3-7-weeks of age. At 7-weeks they were stimulated, mated and the zygotes were cultured in-vitro. Three and 7-weeks old mice were untreated controls. Identical groups were sacrificed without stimulation. Ovaries were analysed for follicular composition. Respiratory-chain (RC) activity and reactive-oxygen-species (ROS) production were measured in brains and livers. RESULTS: Seven-weeks-old mice produced fewer oocytes/embryos than 3-week-old mice. At 7-weeks, mice exposed to NP-10 produced more oocytes/embryos the controls. Their ovaries contained more primordial/primary follicles, with a lower rate of proliferation and fewer antral follicles. There were no differences in follicular apoptosis, RC-activity or ROS production. CONCLUSIONS: In this model, exposure to NP-10 inhibited the spontaneous follicular recruitment, the first report of successful inhibition of physiologic ovarian aging, to the best of our knowledge.