Opposing roles of insulin-like growth factor binding protein 3 and humanin in the regulation of testicular germ cell apoptosis.
Modulating germ cell death and survival have significant therapeutic potential for male infertility and contraception. We have shown previously that IGF binding protein 3 (IGFBP3) gene expression is up-regulated in human testis when germ cell apoptosis is induced by intratesticular hormonal deprivation created by testosterone administration. Humanin (HN) is a binding partner of IGFBP3, and both are expressed in rat testes. We therefore hypothesized that IGFBP3, a proapoptotic factor, and HN, an antiapoptotic factor, are important regulators of male germ cell apoptosis. Whereas baseline apoptosis in the testis was equivalent between Igfbp3 knockout and wild-type mice, treatment with GnRH antagonist (GnRH-A) for 2 wk induced germ cell apoptosis in wild type, which was dramatically reduced in Igfbp3 knockout mice. To investigate the direct effects of IGFBP3 and HN on germ cell apoptosis, intratesticular administration of IGFBP3 for 5 d in rats induced a 4.2- and 3.8-fold increase in apoptosis at stages VII-VIII and XIV-I of the seminiferous epithelium cycle, respectively. GnRH-A treatment for 5 d increased apoptosis, mainly at stages VII-VIII. Addition of IGFBP3 to GnRH-A treatment enhanced apoptosis to 39.3-fold at stages VII-VIII, which was higher than either treatment alone. Intratesticular injection of HN significantly decreased GnRH-A-induced apoptosis at stages XIV-I but not stages VII-VIII. We conclude that IGFBP3 and HN play key roles in the coordinated regulation of testicular germ cell homeostasis. Perturbation of this interaction is important in enhancing or preventing germ cell death, providing new targets for future therapies.
Lue
YanHe
Y
Division of Endocrinology, Department of Medicine, Los Angeles Biomedical Research Institute and Harbor-UCLA Medical Center, Torrance, California 90502, USA.
Swerdloff
Ronald
R
Liu
QingHai
Q
Mehta
Hemal
H
Hikim
Amiya Sinha
AS
Lee
Kuk-Wha
KW
Jia
Yue
Y
Hwang
David
D
Cobb
Laura J
LJ
Cohen
Pinchas
P
Wang
Christina
C
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D004336:Drug Antagonism; D005260:Female; D005854:Germ Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives / Q000494:pharmacology; D007279:Injections, Subcutaneous; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D017207:Rats, Sprague-Dawley; D013094:Spermatozoa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D013737:Testis / Q000033:anatomy & histology / Q000187:drug effects / Q000502:physiology
D018972:Insulin-Like Growth Factor Binding Protein 3; D047908:Intracellular Signaling Peptides and Proteins; C427211:humanin; D007987:Gonadotropin-Releasing Hormone; C083781:LHRH, Ala(6)-Gly(10)-ethylamide-