Effect of adenovirus-mediated overexpression of follistatin and extracellular domain of activin receptor type II on gonadotropin secretion in vitro and in vivo.
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.
Leal
Angela M O
AM
Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Takabe
Kazuaki
K
Wang
Lili
L
Donaldson
Cynthia J
CJ
MacConell
Leigh A
LA
Bilezikjian
Louise M
LM
Verma
Inder M
IM
Vale
Wylie
W
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
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