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Mechanistic target of rapamycin (MTOR) signaling during ovulation in mice
Author(s) -
Siddappa Dayananda,
Kalaiselvanraja Anitha,
Bordig Vilceu,
Dupuis Lisa,
Gasperin Bernardo G.,
Roux Philippe P.,
Duggavathi Raj
Publication year - 2014
Publication title -
molecular reproduction and development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.745
H-Index - 105
eISSN - 1098-2795
pISSN - 1040-452X
DOI - 10.1002/mrd.22333
Subject(s) - pi3k/akt/mtor pathway , biology , endocrinology , medicine , corpus luteum , ovulation , rptor , ovary , microbiology and biotechnology , signal transduction , hormone
SUMMARY A complex network of endocrine/paracrine signals regulates granulosa‐cell function in ovarian follicles. Mechanistic target of rapamycin (MTOR) has recently emerged as a master intracellular integrator of extracellular signals and nutrient availability. The objectives of the present study were to characterize the expression pattern and kinase activity of MTOR during follicular and corpus luteum development, and to examine how inhibition of MTOR kinase activity affects preovulatory maturation of ovarian follicles. MTOR expression was constitutive throughout follicular and corpus luteum development. Gonadotropins induced MTOR kinase activity in the ovary, which was inhibited by rapamycin treatment (10 µg/g body weight, intraperitoneal injection). Inhibition of human chorionic gonadotropin (hCG)‐induced MTOR activity during preovulatory follicle maturation did not change key events of ovulation. Granulosa cells of rapamycin‐treated mice showed reduced MTOR kinase activity at 1 and 4 hr post‐hCG and overexpression of hCG‐induced ovulation genes at 4 hr post‐hCG. Overexpression of these ovulatory genes was associated with hyper‐activation of extracellular signal‐regulated kinase 1/2 (ERK1/2), which occurred in response to inhibition of MTOR with rapamycin and suggested that MTOR may function as a negative regulator of the mitogen‐activated protein kinase (MAPK) pathway. Indeed, simultaneous inhibition of MTOR and ERK1/2 activities during preovulatory follicle maturation caused anovulation. Inhibition of hCG‐induced ERK1/2 activity alone suppressed MTOR kinase activity, indicating that MAPK pathway is upstream of MTOR. Thus, normal ovulation appears to be a result of complex interactions between MTOR and MAPK signaling pathways in granulosa cells of ovulating follicles in mice. Mol. Reprod. Dev . 81: 655–665, 2014. © 2014 Wiley Periodicals, Inc.