The Hippo Pathway Effectors YAP and TAZ Regulate LH Release by Pituitary Gonadotrope Cells in Mice

Abstract

The Hippo transcriptional coactivators YAP and TAZ exert critical roles in morphogenesis, organ size determination and tumorigenesis in many tissues. Although Hippo kinase cascade activity was recently reported in the anterior pituitary gland in mice, the role of the Hippo effectors in regulating gonadotropin production remains unknown. The objective of this study was therefore to characterize the roles of YAP and TAZ in gonadotropin synthesis and secretion. Using a conditional gene targeting approach (cKO), we found that gonadotrope-specific inactivation of Yap and Taz resulted in increased circulating levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in adult male mice, along with increased testosterone levels and testis weight. Female cKO mice had increased circulating LH (but not FSH) levels, which were associated with a hyperfertility phenotype characterized by higher ovulation rates and larger litter sizes. Unexpectedly, the loss of YAP/TAZ did not appear to affect the expression of gonadotropin subunit genes, yet both basal and GnRH-induced LH secretion were increased in cultured pituitary cells from cKO mice. Likewise, pharmacologic inhibition of YAP binding to the TEAD family of transcription factors increased both basal and GnRH-induced LH secretion in LβT2 gonadotrope-like cells in vitro without affecting Lhb expression. Conversely, mRNA levels of ChgA and SgII, which encode key secretory granule cargo proteins, were decreased following pharmacologic inhibition of YAP/TAZ, suggesting a mechanism whereby YAP/TAZ regulate the LH secretion machinery in gonadotrope cells. Together, these findings represent the first evidence that Hippo signaling may play a role in regulating pituitary LH secretion.

Neuromedin S Regulates Steroidogenesis through Maintaining Mitochondrial Morphology and Function via NMUR2 in Goat Ovarian Granulosa Cells

“…Furthermore, many neuroregulatory substances have been demonstrated to be related to the Hippo pathway and involved in various physiological functions. The Hippo pathway participates in the luteinizing hormone [ 40 ] and gonadotropin-releasing hormone [ 41 ] secretion in gonadotrope cells. The neuropeptide Galanin contributes to cholangiocyte proliferation through activation of the Hippo pathway [ 42 ].…”

A salmon fish model reveals genetic signals in brain associated with early maturation

“…Furthermore, we explored whether these vgll3-associated transcriptional changes in the brain could have the capacity for detecting early maturation before any visible signs of maturation emerge in the testis. This is particularly interesting because the molecular signal regulated by vgll3 (the Hippo pathway) is active and plays different roles in all the brain regions involved in sexual maturation (Lodge et al 2016;Beck and Kressel 2020;Lalonde-Larue et al 2022). In addition, the Hippo pathway is the mediator of fatty diet-induced transcriptional changes in different tissues including brain and particularly hypothalamus (Poon et al 2013).…”

“…This is particularly interesting because the molecular signal regulated by vgll3 (the Hippo pathway) is active and plays different roles in all the brain regions involved in sexual maturation (Lodge et al . 2016; Beck and Kressel 2020; Lalonde-Larue et al . 2022).…”