Granulosa Cell-Expressed BMPR1A and BMPR1B Have Unique Functions in Regulating Fertility but Act Redundantly to Suppress Ovarian Tumor Development

Abstract

Bone morphogenetic proteins (BMPs) have diverse roles in development and reproduction. Although several BMPs are produced by oocytes, thecal cells, and granulosa cells of developing follicles, the in vivo functions of most of these ligands are unknown. BMP signals are transduced by multiple type I and type II TGFbeta family receptors, and of the type I receptors, BMP receptor 1A (BMPR1A) and BMP receptor 1B (BMPR1B) are known to be expressed in rodent granulosa cells. Female mice homozygous null for Bmpr1b are sterile due to compromised cumulus expansion, but the function of BMPR1A in the ovary is unknown. To further decipher a role for BMP signaling in mouse granulosa cells, we deleted Bmpr1a in the granulosa cells of the ovary and found Bmpr1a conditional knockout females to be subfertile with reduced spontaneous ovulation. To explore the redundant functions of BMP receptor signaling in the ovary, we generated Bmpr1a Bmpr1b double-mutant mice, which developed granulosa cell tumors that have evidence of increased TGFbeta and hedgehog signaling. Thus, similar to SMAD1 and SMAD5, which have redundant roles in suppressing granulosa cell tumor development in mice, two type I BMP receptors, BMPR1A and BMPR1B, function together to prevent ovarian tumorigenesis. These studies support a role for a functional BMP signaling axis as a tumor suppressor pathway in the ovary, with BMPR1A and BMPR1B acting downstream of BMP ligands and upstream of BMP receptor SMADs.

FOXL2: a central transcription factor of the ovary

“…Interestingly, deletion of Smad1 and Smad5 in GCs leads to a similar phenotype, suggesting that the BMP/SMAD pathway is required to control GC proliferation (Pangas et al 2008). This is confirmed by the observation that a double Bmpr1a/Bmpr1b knockout also leads to GCT formation (Edson et al 2010). …”

A MicroRNA-124 Polymorphism is Associated with Fracture Healing via Modulating BMP6 Expression

“…Several members of the family are key molecules in events such as odontogenesis and limb bud development [23-25]. BMPs in growth plate are also believed to promote maturation, as well as programmed cell death, or apoptosis [23, 26-28].…”

Small molecule inhibitor of the bone morphogenetic protein pathway DMH1 reduces ovarian cancer cell growth

“…For example, treatment of ovarian cancer cells with recombinant BMP-2 has an anti-proliferative effect [14] and constitutively active BMPR1a receptor activity limits metastasis of ovarian cancer cells through decreased adhesion [25]. Additionally, the BMP receptors BMPR1a and BMPR1b have redundant roles that can suppress ovarian tumor formation [26]. Conversely, BMP tumor promoting activity has been demonstrated in both ovarian tumor cells and the surrounding microenvironment [27; 28].…”