The transforming growth factor 2 (TGF2) superfamily, the largest family of secreted proteins in mammals, includes the bone morphogenetic proteins (BMPs), actives, and myostatin. These ligands signal through a heteromeric complex of type 1 and type 2 serine/threonine kinase receptors. Ligand-induced dimerization of these receptors leads to phosphorylation of receptor-regulated SMAD proteins, which translocate to the nucleus with SMAD4 to regulate gene expression. These signaling pathways have been implicated in many pathophysiologic processes. For example, at the end of the first trimester, activin A levels are elevated in women who will eventually develop preeclampsia, and the BMP/activin/myostatin type 2 receptor, ACVR2A, has been identified as a candidate maternal susceptibility gene for preeclampsia. With the support of this grant that started in 1994, we have generated and analyzed mice with mutations in activin subunits, a ligand binding protein (follistatin), a downstream receptor-binding protein (FKBP12), several SMADs, and multiple BMP/activin/myostatin receptors. The phenotypes of our genetic models range from neonatal lethality to infertility to cancer. These models have been indispensable for deciphering TGF2 superfamily signaling pathways in the gonads and modeling clinical reproductive diseases including infertility, premature ovarian failure, and ovarian and testicular cancer. These HD32067-supported studies have resulted in 43 papers published during the current grant period and 87 publications overall including high impact papers in Nature, Nature Genetics, Nature Medicine, Science, Genes and Development, and Developmental Cell. The overall goals of this R01 renewal will be to follow-up these studies by analyzing the unique and redundant roles of the type 1 and type 2 receptors in BMP signaling in the uterus and identifying new agents for inhibiting and/or mimicking the functions of BMPs, activins and myostatin in uterine, ovarian, muscle, and bone physiology.
The Specific Aims of these proposed studies are: 1) Define the BMP receptor pathways in implantation and post- implantation uterine biology, and 2) Identify and synthesize small molecule BMP receptor-specific antagonists and agonists. These proposed studies will allow us to genetically place TGF2 superfamily ligands, receptors, and downstream SMADs into biological pathways in the female reproductive tract, and identify and synthesize compounds for future treatments of human reproductive and non-reproductive diseases.

Public Health Relevance

The transforming growth factor 2 (TGF2) superfamily is the largest family of secreted proteins in mammals, and TGF2 signaling pathways have been implicated in a diversity of developmental and pathophysiological processes including preeclampsia. Over the last 19 years, we have used multiple in vivo and in vitro approaches to dissect the essential and redundant roles of these signaling pathways. The objectives of this R01 renewal are to mechanistically define the unique and redundant roles of the bone morphogenetic protein (BMP) type 1 and type 2 receptors during implantation and post-implantation and to identify new drugs for inhibiting or mimicking the functions of BMPs, activins, and myostatin for treatments of clinically important reproductive and non-reproductive diseases.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Pregnancy and Neonatology Study Section (PN)
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Yoshinaga, Koji
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Baylor College of Medicine
Schools of Medicine
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Clementi, Caterina; Tripurani, Swamy K; Large, Michael J et al. (2013) Activin-like kinase 2 functions in peri-implantation uterine signaling in mice and humans. PLoS Genet 9:e1003863
Nagashima, Takashi; Li, Qinglei; Clementi, Caterina et al. (2013) BMPR2 is required for postimplantation uterine function and pregnancy maintenance. J Clin Invest 123:2539-50
Matzuk, Martin M; Burns, Kathleen H (2012) Genetics of mammalian reproduction: modeling the end of the germline. Annu Rev Physiol 74:503-28
Gokoffski, Kimberly K; Wu, Hsiao-Huei; Beites, Crestina L et al. (2011) Activin and GDF11 collaborate in feedback control of neuroepithelial stem cell proliferation and fate. Development 138:4131-42
Nagashima, Takashi; Kim, Jaeyeon; Li, Qinglei et al. (2011) Connective tissue growth factor is required for normal follicle development and ovulation. Mol Endocrinol 25:1740-59
Roy, Angshumoy; Matzuk, Martin M (2011) Reproductive tract function and dysfunction in women. Nat Rev Endocrinol 7:517-25
Lee, Se-Jin; Lee, Yun-Sil; Zimmers, Teresa A et al. (2010) Regulation of muscle mass by follistatin and activins. Mol Endocrinol 24:1998-2008
Su, You-Qiang; Sugiura, Koji; Li, Qinglei et al. (2010) Mouse oocytes enable LH-induced maturation of the cumulus-oocyte complex via promoting EGF receptor-dependent signaling. Mol Endocrinol 24:1230-9
Mithraprabhu, Sridurga; Mendis, Sirisha; Meachem, Sarah J et al. (2010) Activin bioactivity affects germ cell differentiation in the postnatal mouse testis in vivo. Biol Reprod 82:980-90
Rajanahally, Saneal; Agno, Julio E; Nalam, Roopa L et al. (2010) Genetic evidence that SMAD2 is not required for gonadal tumor development in inhibin-deficient mice. Reprod Biol Endocrinol 8:69

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