NFATc1/αA and Blimp-1 Support the Follicular and Effector Phenotype of Tregs

CD4+CXCR5+Foxp3+ T-follicular regulatory (TFR) cells control the germinal center responses. Like T-follicular helper cells, they express high levels of Nuclear Factor of Activated T-cells c1, predominantly its short isoform NFATc1/αA. Ablation of NFATc1 in Tregs prevents upregulation of CXCR5 and migration of TFR cells into B-cell follicles. By contrast, constitutive active NFATc1/αA defines the surface density of CXCR5, whose level determines how deep a TFR migrates into the GC and how effectively it controls antibody production. As one type of effector Treg, TFR cells express B lymphocyte-induced maturation protein-1 (Blimp-1). Blimp-1 can directly repress Cxcr5 and NFATc1/αA is necessary to overcome this Blimp-1-mediated repression. Interestingly, Blimp-1 even reinforces the recruitment of NFATc1 to Cxcr5 by protein-protein interaction and by those means cooperates with NFATc1 for Cxcr5 transactivation. On the contrary, Blimp-1 is necessary to counterbalance NFATc1/αA and preserve the Treg identity. This is because although NFATc1/αA strengthens the follicular development of Tregs, it bears the inherent risk of causing an ex-Treg phenotype.

Characterization of XR_311113.2 as a MicroRNA Sponge for Pre-ovulatory Ovarian Follicles of Goats via Long Noncoding RNA Profile and Bioinformatics Analysis

Long noncoding RNAs (lncRNAs) were identified recently as a large class of noncoding RNAs (ncRNAs) with a length ≥200 base pairs (bp). The function and mechanism of lncRNAs have been reported in a growing number of species and tissues. In contrast, the regulatory mechanism of lncRNAs in the goat reproductive system has rarely been reported. In the present study, we sequenced and analyzed the lncRNAs using bioinformatics to identify their expression profiles. As a result, 895 lncRNAs were predicted in the pre-ovulatory ovarian follicles of goats. Eighty-eight lncRNAs were differentially expressed in the Macheng black goat when compared with Boer goat. In addition, the lncRNA XR_311113.2 acted as a sponge of chi-miR-424-5p, as assessed via a luciferase activity assay. Taken together, our findings demonstrate that lncRNAs have potential effects in the ovarian follicles of goats and may represent a promising new research field to understand follicular development.

Comparative Analysis Among Different Species Reveals That the Androgen Receptor Regulates Chicken Follicle Selection Through Species-Specific Genes Related to Follicle Development

The differences in reproductive processes at the molecular level between viviparous and oviparous animals are evident, and the site in the ovary that synthesizes sex hormones (androgens and oestrogens) and the trends for enriching sex hormones during follicle development in chickens are different from those in mammals, suggesting that the effect of sex hormones on follicle development in chickens is probably different from that in viviparous animals. To explore the specific role of androgen receptors (ARs) on chicken follicular development, we matched the correspondence of follicular development stages among chickens, humans, cows and identified chicken-specific genes related to follicle development (GAL-SPGs) by comparing follicle development-related genes and their biological functions among species (chickens, humans, and cows). A comparison of the core transcription factor regulatory network of granulosa cells (or ovaries) based on super-enhancers among species (chicken, human, and mouse) revealed that AR is a core transcriptional regulator specific to chickens. In vivo experiments showed that inhibition of AR significantly reduced the number of syf (selected stage follicles) in chickens and decreased the expression of GAL-SPGs in F5 follicles, while in vitro experiments showed that inhibition of AR expression in chicken granulosa cells (GCs) significantly down-regulated the expression levels of GAL-SPGs, indicating that AR could regulate follicle selection through chicken-specific genes related to follicle development. A comparison among species (77 vertebrates) of the conserved genomic regions, where chicken super-enhancers are located, revealed that the chicken AR super-enhancer region is conserved in birds, suggesting that the role of AR in follicle selection maybe widespread in birds. In summary, we found that AR can regulate follicle selection through chicken-specific genes related to follicle development, which also emphasizes the important role of AR in follicle selection in chickens and provides a new perspective for understanding the unique process of follicle development in chickens. Our study will contribute to the application of androgens to the control of egg production in chickens and suggests that researchers can delve into the mechanisms of follicle development in birds based on androgen/androgen receptors.

Climate Change and Livestock Fertility

Climate change is a global threat to livestock sector to so many species and ecosystem in different parts of the world. Climate change, heat stress, and nutritional stress are the major intriguing factors responsible for reduced fertility in farm animals in tropical countries. Heat and nutritional stresses affect the reproductive performance by decreasing the expression of estrous behavior, altering ovarian follicular development and hormonal profiles, compromising oocyte competence, and inhibiting embryonic development in livestock. Climate is changed by greenhouse gases that released into atmosphere through man-made activities. Livestock contribute 18% of the production of greenhouse gases itself and causes climate change including heat stress, which has direct and indirect impact on fertility of the animals as well as reduce milk production. Adaptation to climate change and lowering its negative effect by alteration of animal micro-environment using different essential technologies are the main mitigation strategies to recover heat stress damage in this respect.

Viral Infection of the Reproductive System in Times of COVID-19

Coronavirus (SARS-COV2) caused several deaths worldwide. This virus infects the target cell by binding to angiotensin-converting enzymes 2 (ACE2) receptor through its receptor-binding domain (RBD) and replicates. Thus, a high level of ACE2 expression is detected in the testicular cells so that the testis is believed to count as a potential target for direct damage by COVID-19. Moreover, the possibility of testicular damage may be caused by either direct viral invasion through interaction with ACE2 receptors or because of inflammatory response. Similarly, in women, literature reported the distribution and function of ACE2 in the female reproductive system, which is widely expressed in the ovary, uterus, vagina, and placenta. It regulates follicular development and ovulation, modulates luteal angiogenesis and degeneration, and influences regular changes in endometrial tissue and embryo development. Taking these functions into account, COVID-19 may disturb the female reproductive functions through regulating ACE2, resulting in infertility, menstrual disorder, and fetal distress.

Exosomal miR-143-3p Derived from PCOS Follicular Fluid Induces Granulosa Cell Apoptosis by Targeting BMPR1A and Suppression of Smad1/5/8 Signaling

Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorders disease in women of reproductive age. The anovulation caused by abnormal follicular development is still the main characteristic of infertile patients with PCOS. Granulosa cells (GCs), an important component of follicular microenvironment, affect follicular development through GCs dysfunction. Increasing evidence indicates that exosomal miRNAs derived from follicular fluid (FF) of patients play critical roles during PCOS. However, which and how follicular fluid derived exosomal miRNAs play a pivotal role in controlling granulosa cells function and consequently follicular development remain largely unknown. Herein, we showed that miR-143-3p is highly expressed in follicular fluid exosomes of PCOS patients and can be delivered into granulosa cells. Furthermore, the functional experiments showed that the translocated miR-143-3p promoted granulosa cell apoptosis, which are important in follicle development. In terms of mechanism, we demonstrated that BMPR1A was identified as a direct target of miR-143-3p. Overexpression of BMPR1A reversed the effects of exosomal miR-143-3p on GCs apoptosis and proliferation by activating Smad1/5/8 signaling pathway. These results demonstrate that miR-143-3p-containing exosomes derived from PCOS follicular fluid promoted granulosa cell apoptosis by targeting BMPR1A and blockading Smad1/5/8 signaling pathway. Our findings provide a novel mechanism underlying the roles of exosomal-miRNA in follicular fluid of PCOS and facilitate the development of therapeutic strategies for PCOS.

The two-step process of ovarian follicular growth and maturation in mammals can be compared to a fruit ripening where quality depends on the second step

In human IVF, the main uncertainty factor impacting on success is oocyte quality, which largely depends on the follicular status at the time of collection. Decades of debate ensued to find the perfect stimulation protocol demonstrated the complexity of the ovarian response to exogenous gonadotropins and the dynamic nature of late folliculogenesis. Although several follicular markers, proteins, RNA from granulosa cells or microRNA and follicular fluid metabolites have been associated with outcome, the possibility to influence them during stimulation remains elusive. The heterogeneity of the follicle’s maturity following control ovarian stimulation is also an important factor to explain average poor oocyte quality still observed today. In this review, the analogy between the apple ripening on the tree and follicular development is presented to focus the attention on a biphasic process: growth and differentiation. The molecular analysis of the progressive follicular differentiation indicates 2 competing phenomena: growth and differentiation where a delicate balance must operate from one to the other to ensure proper maturity at ovulation. As long as FSH stimulates growth, follicles remain green, and it is only when FSH is replaced by LH that the ripening process begins, and “apples” become red. Both fruits, follicles and apples, depend on a perfect timing of events to generate offspring.