Gonadotropin-Releasing Hormone Induces miR-132 and miR-212 to Regulate Cellular Morphology and Migration in Immortalized LβT2 Pituitary Gonadotrope Cells

Abstract

GnRH is central to the regulation of reproductive function. It acts on pituitary gonadotropes to stimulate LH and FSH synthesis and secretion. We had previously presented evidence for translational control of LHβ synthesis; therefore we investigated whether micro-RNAs might play a role in GnRH regulation in LβT2 cells. We show here that GnRH strongly induces the AK006051 gene transcript that encodes two micro-RNAs, miR-132 and miR-212, within the first intron. We show furthermore that the AK006051 promoter region is highly GnRH responsive. We verify that the p250Rho GTPase activating protein (GAP) is a target of miR-132/212 and show that GnRH treatment leads to a decrease in mRNA and protein expression. This reduction is blocked by an anti-miR to miR-132/212 and mimicked by a pre-miR-132. GnRH inhibits p250RhoGAP expression through a miR-132/212 response element within the 3'-untranslated region. The loss of p250RhoGAP expression leads to activation of Rac and marked increases in both the number and length of neurite-like processes extending from the cell. Knockdown of p250RhoGAP by small interfering RNA induces the same morphological changes observed with GnRH treatment. In addition, loss of p250RhoGAP causes an increase in cellular motility. Our findings suggest a novel pathway regulating long-term changes in cellular motility and process formation via the GnRH induction of miR-132/212 with the subsequent down-regulation of p250RhoGAP.

Gonadotropin releasing hormone activation of the mTORC2/Rictor complex regulates actin remodeling and ERK activity in LβT2 cells

“…Rac1 has been shown to directly bind mTOR and facilitate its activation and localization to plasma membrane microdomains (Saci et al, 2011). Previous work by Godoy et al suggests that GnRH activates Rho family members through microRNA regulation of p250RhoGAP to mediate cell morphology and migration in LβT2 cells (Godoy, Nishimura and Webster, 2011). Other work in heterologous HEK293 cells transfected with GnRHR reveals that GnRH-induced Rac1 activation is important for phosphorylation and recruitment of focal adhesion kinase (FAK) to focal adhesions (Davidson, Pawson, Millar et al, 2004).…”

Follicular fluid and mural granulosa cells microRNA profiles vary in in vitro fertilization patients depending on their age and oocyte maturation stage

“…In our in silico prediction, we observed that several miRNAs were assigned to gene ontology processes termed as ''GnRH signaling pathway'' (among others). Previous studies have proven the effect of miRNA in GnRH signaling and also the effect of GnRH signaling in miRNA expression patterns (55)(56)(57)(58). The potential gene targets related to this process included kinases and calcium and MAPK signaling pathways, which are involved in FSH and LH production, which in turn could be affecting proper timing for oocyte meiosis and maturation.…”

A mikro-RNS-ek szerepe az agyalapimirigy-daganatok tumorbiológiájában

“…Egy másik tanulmány-ban az egér központi idegrendszerének különböző részeit vizsgálva sikerült agyalapimirigyre specifikus miRNS-eket azonosítani [22]. Amellett, hogy a miRNSeknek az emberben is fontos szerepük van a normál mirigy fejlődésében [19,23,24] és hormontermelésében [25][26][27][28][29][30][31], az elmúlt években egyre több humán vizsgálat támasztja alá azt is, hogy részt vehetnek az adenomák kialakulásában és növekedésében [32][33][34][35].…”