Bone morphogenetic protein 2 signals via BMPR1A to regulate murine follicle-stimulating hormone beta subunit transcription.
Follicle-stimulating hormone beta subunit (Fshb) expression is regulated by transforming growth factor beta superfamily ligands. Recently, we demonstrated that bone morphogenetic proteins (BMPs) stimulate Fshb transcription alone and in synergy with activins. Also, transfection of the BMP type II receptor (BMPR2) and constitutively active forms of the type I receptors (activin A receptor type I [ACVR1] or BMP receptor type IA [BMPR1A]) in immortalized gonadotroph cells (LbetaT2) stimulated murine Fshb promoter-reporter activity. A third type I receptor (BMP receptor type IB [BMPR1B]) is also expressed in LbetaT2 cells, but we did not previously assess its functional role. A point mutation in BMPR1B (Q249R) is associated with increased ovulation rates and elevated FSH levels in Booroola (FecB) sheep. Herein, we assessed whether BMPR1B can regulate Fshb transcription in LbetaT2 cells and whether its ability to do so is altered by the Q249R mutation. As with ACVR1 and BMPR1A, coexpression of BMPR1B with BMPR2 increased Fshb promoter-reporter activity in BMP2-dependent and BMP2-independent fashions. Unexpectedly, the BMPR1B-Q249R mutant was equivalent to the wild type in its ability to stimulate SMAD1/5 phosphorylation and Fshb transcription. Pharmacological inhibition of ACVR1, BMPR1A, and BMPR1B confirmed that one or more of these receptors are required for BMP2-stimulated SMAD1/5 phosphorylation and Fshb reporter activity. Knockdown of endogenous BMPR1A, but not ACVR1 or BMPR1B, significantly impaired the synergism of BMP2 with activin A. Collectively, these data suggest that BMPR1A is the preferred BMP2 type I receptor in LbetaT2 cells and that neither ACVR1 nor BMPR1B compensates for its loss. The specific mechanism(s) through which the Booroola FecB mutation alters BMPR1B function remains to be determined.
Ho
Catherine C
CC
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
Bernard
Daniel J
DJ
D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism / Q000502:physiology*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D037201:Follicle Stimulating Hormone, beta Subunit / Q000235:genetics*; D005786:Gene Expression Regulation; D052681:Gonadotrophs / Q000378:metabolism; D006801:Humans; D051379:Mice; D020125:Mutation, Missense / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics; D014158:Transcription, Genetic; D014162:Transfection
D055396:Bone Morphogenetic Protein 2; D037201:Follicle Stimulating Hormone, beta Subunit; D052005:Bone Morphogenetic Protein Receptors, Type I