This Program Project of 20 years comprising 4 Projects and 4 Cores explores the reproductive roles and signaling mechanisms of protein/peptides originally characterized by virtue of their regulatory roles on gonadotropes. We concentrate on activin and inhibin, which reciprocally modulate FSH production, and the hypothalamic neuropeptide, GnRH, which stimulates acute secretion of both LH and FSH. A unifying theme within each Project is the structural and functional characterization of ligand/receptor interactions. Project I (Vale) WILL: Investigate the nature and signaling of the heteromeric complex comprising activin and two types of activin receptor serine kinases; Explore mechanisms that counter regulate activin at the receptor level (inhibin) and intracellularly (Smad7); Examine the local autocrine and paracrine regulation of gonadotropes. Dr. Choe's Project has recently solved the X-ray crystallographic structure of the Type II receptor extracellular ligand binding domain and found it to have a highly unexpected three-fingered toxin fold, providing hypotheses for exploring the structural requirements of ligand recognition that are being tested by Projects I, III and IV. This Project proposes to elucidate the structure of the triple complex comprising activin and its Type II and Type I receptors. Dr. Fischer's Project uses computer modeling and x-ray structure analysis (Project III) to design mutant activin proteins which will be used to test hypotheses regarding interactions with type II and I activin receptors and follistatin. One core generates and provides well- characterized polyclonal antisera towards activin signaling molecules and conducts radioimmunoassays for gonadotropins. The next core (Fischer) prepares large quantities of recombinant proteins needed by the Program and characterized primary structure and disulfide arrangement of proteins. The last core prepares and characterizes synthetic peptides for use as antigens or in biological studies. This Program brings together a diversity of experts a approaches to address fundamental questions of neuroendocrine, endocrine, paracrine and autocrine signaling. Because of the importance of activin/inhibin and GnRH in fertility regulation and reproductive medicine, it is likely that these basic studies conducted in this Program will continue to yield practical benefits.
| Kim, Meejung; Choe, Senyon (2011) BMPs and their clinical potentials. BMB Rep 44:619-34 |
| Muenster, Uwe; Korupolu, Radhika; Rastogi, Ratindra et al. (2011) Antagonism of activin by activin chimeras. Vitam Horm 85:105-28 |
| Looyenga, Brendan D; Wiater, Ezra; Vale, Wylie et al. (2010) Inhibin-A antagonizes TGFbeta2 signaling by down-regulating cell surface expression of the TGFbeta coreceptor betaglycan. Mol Endocrinol 24:608-20 |
| Valera, Elvira; Isaacs, Michael J; Kawakami, Yasuhiko et al. (2010) BMP-2/6 heterodimer is more effective than BMP-2 or BMP-6 homodimers as inductor of differentiation of human embryonic stem cells. PLoS One 5:e11167 |
| Isaacs, Michael J; Kawakami, Yasuhiko; Allendorph, George P et al. (2010) Bone morphogenetic protein-2 and -6 heterodimer illustrates the nature of ligand-receptor assembly. Mol Endocrinol 24:1469-77 |
| Hassold, Terry; Hunt, Patricia (2009) Maternal age and chromosomally abnormal pregnancies: what we know and what we wish we knew. Curr Opin Pediatr 21:703-8 |
| Wiater, Ezra; Lewis, Kathy A; Donaldson, Cynthia et al. (2009) Endogenous betaglycan is essential for high-potency inhibin antagonism in gonadotropes. Mol Endocrinol 23:1033-42 |
| Cheng, Edith Y; Hunt, Patricia A; Naluai-Cecchini, Theresa A et al. (2009) Meiotic recombination in human oocytes. PLoS Genet 5:e1000661 |
| Ciarmela, Pasquapina; Wiater, Ezra; Smith, Sean M et al. (2009) Presence, actions, and regulation of myostatin in rat uterus and myometrial cells. Endocrinology 150:906-14 |
| Blount, Amy L; Vaughan, Joan M; Vale, Wylie W et al. (2008) A Smad-binding element in intron 1 participates in activin-dependent regulation of the follistatin gene. J Biol Chem 283:7016-26 |
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