title: Effect of adenovirus-mediated overexpression of follistatin and extracellular domain of activin receptor type II on gonadotropin secretion in vitro and in vivo.
abstract: Activins are dimeric proteins that stimulate the synthesis and secretion of pituitary FSH by interacting with two classes of receptors, type I and type II, to initiate their intracellular signaling cascade. The extracellular domain of type II activin receptor (ActRII-ECD) contains all structural determinants sufficient for high affinity ligand binding. A soluble recombinant ActRII-ECD has been reported to attenuate FSH secretion from cultured rat anterior pituitary cells in response to exogenous activin A or endogenous activin B. Follistatin is a binding protein that acts as an extracellular factor to bind and inactivate activin. We constructed adenoviral vectors able to mediate expression of follistatin 288 (AdexCAFS288) and ActRII-ECD (AdexCAECD) and tested their biological activities both in vitro and in vivo. The data show that adenovirus-mediated overexpression of either ActRII-ECD or follistatin was able to attenuate FSH secretion by cultured rat anterior pituitary cells. However, AdexCAFS288 overexpression of follistatin was more effective than adenovirus-mediated overexpression of ActRII-ECD. In vivo, a single ip injection of AdexCAFS288 induced the expression of high levels of follistatin and resulted in the suppression of serum FSH levels in castrated male rats for up to 12 d postinjection. Infection with AdexCAFS288 had no effect on LH secretion in vitro or in vivo, demonstrating its selectivity. In conclusion, the results demonstrate the effectiveness of adenovirus-mediated overexpression of follistatin and ActRII-ECD to regulate FSH secretion and the potential of using this strategy as a tool to further define the critical role of activin/inhibin/follistatin circuitry in the modulation of the reproductive system.
authors.affiliation: Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
authors.forename: Angela M O
authors.initials: AM
authors.lastname: Leal
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Takabe
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Donaldson
authors.forename: Leigh A
authors.initials: LA
authors.lastname: MacConell
authors.forename: Louise M
authors.initials: LM
authors.lastname: Bilezikjian
authors.forename: Inder M
authors.initials: IM
authors.lastname: Verma
authors.forename: Wylie
authors.initials: W
authors.lastname: Vale
mesh_terms: D030301:Activin Receptors, Type II / Q000096:biosynthesis* / Q000235:genetics; D028341:Activins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D000256:Adenoviridae / Q000235:genetics*; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D005640:Follicle Stimulating Hormone / Q000378:metabolism; D038681:Follistatin; D006062:Gonadotropins / Q000378:metabolism*; D007265:Inhibins / Q000502:physiology; D009919:Orchiectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D014779:Virus Replication / Q000235:genetics
chemical_list: D038681:Follistatin; D006062:Gonadotropins; D028341:Activins; D007265:Inhibins; D000324:Adrenocorticotropic Hormone; D005640:Follicle Stimulating Hormone; D030301:Activin Receptors, Type II; C425585:activin receptor type II-A