Welcoming β-Catenin to the Gonadotropin-Releasing Hormone Transcriptional Network in Gonadotropes

Abstract

GnRH binds its G-coupled protein receptor, GnRHR, on pituitary gonadotropes and stimulates transcription of Cga, Lhb, and Fshb. These three genes encode two heterodimeric glycoprotein hormones, LH and FSH, that act as gonadotropins by regulating gametogenesis and steroidogenesis in both the testes and ovary. GnRH also regulates transcription of Gnrhr. Thus, regulated expression of Cga, Lhb, Fshb, and Gnrhr provides a genomic signature unique to functional gonadotropes. Steadily increasing evidence now indicates that GnRH regulates transcription of its four signature genes indirectly through a hierarchical transcriptional network that includes distinct subclasses of DNA-binding proteins that comprise the immediate early gene (IEG) family. These IEGs, in turn, confer hormonal responsiveness to the four signature genes. Although the IEGs confer responsiveness to GnRH, they cannot act alone. Instead, additional DNA-binding proteins, including the orphan nuclear receptor steroidogenic factor 1, act permissively to allow the four signature genes to respond to GnRH-induced changes in IEG levels. Emerging new findings now indicate that beta-catenin, a transcriptional coactivator and member of the canonical WNT signaling pathway, also plays an essential role in transducing the GnRH signal by interacting with multiple DNA-binding proteins in gonadotropes. Herein we propose that these interactions with beta-catenin define a multicomponent transcriptional network required for regulated expression of the four signature genes of the gonadotrope, Cga, Lhb, Fshb, and Gnrhr.

Molecular characterisation and functional interrogation of a local natriuretic peptide system in rodent pituitaries, αT3-1 and LβT2 gonadotroph cells

“…implicated (Surendran & Simon 2003). We have not examined the role of Wnt signalling in regulating CNP expression in the pituitary, yet recent observations of GNRH-dependent b-catenin signalling in gonadotrophs (Salisbury et al 2008) suggest this pathway could be an alternative regulator of Nppc transcription in the pituitary.…”

ANE syndrome caused by mutated RBM28 gene: a novel etiology of combined pituitary hormone deficiency

“…Interestingly, recent data have established a major role for the Wnt/ b-catenin signaling pathway in regulating pituitary development and growth (21). These studies demonstrated that b-catenin plays an essential role in transducing the GnRH signal by interacting with multiple DNA-binding proteins in gonadotropes (22)(23)(24). In addition, in a mouse model, b-catenin acts as a cofactor for a number of pituitary transcription factors that control pituitary cell specification and exert both stimulatory (prop1 in regulating expression of pit-1) and inhibitory (Hesx1) effects (21,25,26).…”

Pituitary gland and β-catenin signaling: from ontogeny to oncogenesis

“…Further, b-catenin appears as an essential cofactor of SF1, enhancing its synergistic effects with GnRH to stimulate the transcription of LHB/Lhb genes through GnRH-mediated changes in EGR1; thus, optimal LH levels are synthesised to ensure sustained pulsatile secretion (Fig. 2) [51,52]. Over-expression of axin (which after binding to b-catenin initiates its degradation) interferes with the activity of the LHB promoter [52].…”

“…1 b- and its down-regulation with T3 (triiodo-thyronine) treatment for 6 h; the nuclear b-catenin protein and functional b-catenin/TCF response promoter were significantly reduced with T3 treatment, such changes resulting in growth arrest of thyrotroph tumors in vitro [54]. [51]. Interactions between EGR1, SF1, Pitx1 and b-catenin determine the GnRH response mediating LHB/Lhb gene transcription.…”