Anti-Müllerian hormone: a new actor of sexual dimorphism in pituitary gonadotrope activity before puberty.

Anti-Müllerian hormone (AMH) contributes to male sexual differentiation and acts on gonads of both sexes. Identification of AMH receptivity in both pituitary and brain has led to the intriguing idea that AMH participates to the hypothalamic-pituitary control of reproduction, however in vivo experimental evidence is still lacking. We show that AMH stimulates secretion and pituitary gene expression of the gonadotropin FSH in vivo in rats. AMH action is sex-dependent, being restricted to females and occurring before puberty. Accordingly, we report higher levels of pituitary AMH receptor transcripts in immature females. We show that AMH is functionally coupled to the Smad pathway in LßT2 gonadotrope cells and dose-dependently increases Fshb transcript levels. Furthermore, AMH was shown to establish complex interrelations with canonical FSH regulators as it cooperates with activin to induce Fshb expression whereas it reduces BMP2 action. We report that GnRH interferes with AMH by decreasing AMH receptivity in vivo in females. Moreover, AMH specifically regulates FSH and not LH, indicating that AMH is a factor contributing to the differential regulation of gonadotropins. Overall, our study uncovers a new role for AMH in regulating gonadotrope function and suggests that AMH participates in the postnatal elevation of FSH secretion in females.

Tumor suppressor action of liganded thyroid hormone receptor beta by direct repression of beta-catenin gene expression.

The abundance of ß-catenin, which plays a critical role in oncogenesis, is tightly controlled by proteasomal pathways. Its aberrant accumulation is associated with the overactivation of its oncogenic signaling and tumorigenesis in cancers, including thyroid cancer. Our previous studies have suggested that ß-catenin abundance could also be regulated at the transcriptional level by thyroid hormone (T(3)) and thyroid hormone receptor ß (TRß). By using hypothyroid mice supplemented or not with T(3), we showed that T(3) significantly repressed Ctnnb1 expression in vivo in the thyroid. By using two human cell lines, i.e., the thyroid HTori and the cervical cancer HeLa cell lines, each stably expressing TRß, we observed that T(3) induced the down-regulation of CTNNB1 transcript levels. Luciferase reporter assays with various constructs harboring 5' deletion of the CTNNB1 promoter or with mutated thyroid hormone response element (TRE) binding sites, and EMSAs showed that this transrepression was mediated through an interaction between TRß-retinoid X receptor ß complexes and TREs located in the human CTNNB1 promoter between -807 and -772 and consisting of two hexamers separated by 14 nucleotides. The direct regulation of CTNNB1 expression by TRß was further confirmed by chromatin immunoprecipitation assays showing TRß recruitment to the CTNNB1 promoter in thyroid cells. This is the first report demonstrating a direct repression of the ß-catenin gene by liganded TRß through interaction with negative TREs located in CTNNB1 promoter. Importantly, this study uncovers a new molecular mechanism whereby liganded TRß acts as a tumor suppressor via inhibition of the expression of a potent tumor promoter, the CTNNB1 gene.

Unaltered development of the initial follicular waves and normal pubertal onset in female rats after neonatal deletion of the follicular reserve.

In rats, the pool of primordial follicles is established within the first 3 d postnatally (dpn). Immediately after their differentiation, a subset of follicles begins to grow and constitutes the initial follicular waves. In this study we investigated the development of these early growing follicles after deletion of the primordial follicle pool induced by 1.5 Gy gamma-irradiation at 5 dpn. Within only 24 h, i.e. at 6 dpn, 99% of the primordial follicles disappeared, whereas most of the growing follicles remained unaffected. The study of these surviving follicles throughout the immature period has shown that their subsequent growth proceeded normally, as assessed by proliferating cell nuclear antigen immunostaining and follicular counts. No modification in the process of follicular atresia, studied by terminal deoxynucleotidyltransferase-mediated deoxy-UTP-fluorescein nick end labeling and Southern blot of DNA fragmentation analysis, was observed. Complementary analysis, by either in situ hybridization for inhibin subunits, P450 aromatase, and LH receptor mRNAs or plasma dosages of 17beta-estradiol and inhibin B, further showed that follicular maturation was unaltered. In line with these observations, pubertal onset was normal, regarding both age and ovulation rate. Nevertheless, as a consequence of the nonrenewal of the growing pool, the follicular complement was practically exhausted at puberty, and 90% of the females evidenced sterility by 4 months. Altogether, our results demonstrate that the deletion of the primordial follicle pool has induced no modification in the growth pattern of the early growing follicles that develop as their counterparts in control ovaries. Within the immature period, the initial follicular waves ensure the ovarian functionality and thus play a key role in the initiation of reproductive life.