ActRIC involvement in the control of normal lactotroph function and lactotroph hyperplasia development

PEÑA, M.; FARAONI, E Y; ABELEDO MACHADO, A I; BORNANCINI, D; MARCIAL LÓPEZ, C A; RULLI, S B; DIAZ-TORGA, GRACIELA

Congreso; International Congress of Neuroendocrinology; 2022

IntroductionWe have previously described that pituitary activin expression decreased during lactotroph hyperplasia development in two mouse models of prolactinoma. Concomitant, a decrease in protein expression of activin type 1-receptor ActRIB (ALK4) and pp38 was also observed, indicating a downregulation of activins biological activity in lactotroph hyperplasia. In addition, we demonstrated that the loss of gonadal inhibins after a prepuberal ovariectomy (OVX) recovers the expression of pituitary activins, activin receptors, and p-p38 specifically in lactotrophs cells. These results emphasize the importance of the local inhibitory action of activins on lactotroph population. While we were previously focused on activin action through ActRIB involving p-p38 pathway, the participation of the known activin type 1-receptor ActRIC (ALK7), in the control of lactotroph function is still not fully understood.Methods/ResultsWe analyzed the pituitary expression of ActRIC in two mice models: mice overexpressing the β subunit of the human chorionic gonadotrophin (hCGβ+) and mice lacking dopamine type 2 receptor (D2RKO). We used the respective wild-type (WT) mice as controls. These animal models present sex differences: an increase in the pituitary size (lactotroph hyperplasia) and hyperprolactinemia are observed only in adult female transgenic mice, but not in transgenic males.Our results showed that the expression of Acvr1C, by RTqPCR, is decreased in hyperplastic pituitaries from hCGβ+ females, but surprisingly, is increased in hyperplastic pituitaries from D2RKO females. No differences among genotypes were observed in males from these mouse models.We demonstrated the protein ActRIC expression in normal and hyperplastic PRL-secreting cells, analyzed by double immunofluorescence (PRL/ActRIC). We found that ActRIC protein expression is decreased during hyperplasia development in hCGβ+ and D2RKO females when are compared with their respective WTs. A prepuberal OVX, prevented these pituitary alterations in the adulthood, increasing Acvr1C expression in transgenic females from both mouse models, and increasing the number of lactotrophs expressing ActRIC (double IF) (hCGβ+-OVX females), reaching levels even higher than those observed in their WT control littermates.ConclusionsThese results demonstrated the ActRIC expression in the lactotroph population. This expression is downregulated in lactotroph hyperplasia development in two different mouse models, and it is restored after the loss of gonadal inhibins (OVX), concomitant with the recovery of the local activin expression. These results highlight the involvement of ActRIC in the negative control exercised by activins on lactotroph function and hyperplasia development.