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Submitted on December 12, 2005
Accepted on March 6, 2006
Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030 (MS, IH-G, IG-R, JSR); Department of Applied Animal Science, Graduate School of Biosphere Science, Hiroshima University, 1-4-4 Kagamiyama Higashi-Hiroshima, 724-8528, Japan (MS); Departments of Biochemistry and Molecular Biology and Physiology, Faculty of Sciences, University of Las Palmas, 35016 Las Palmas Grand Canaria, Spain (IH-G, IG-R)
* To whom correspondence should be addressed. E-mail: joanner{at}bcm.tmc.edu.
The molecular bridges that link the LH surge with functional changes in cumulus cells that possess few LH receptors are being unraveled. Herein we document that EGF-like factors amphiregulin (Areg), epiregulin (Ereg) and betacellulin (Btc) are induced in cumulus oocyte complexes (COCs) by autocrine and paracrine mechanisms that involve the actions of prostaglandins (PGs) and progesterone receptor (PGR). Areg and Ereg mRNA and protein levels were reduced significantly in COCs and ovaries collected from prostagandin synthase 2 (Ptgs2) null mice and Pgr null (PRKO) mice at 4 h and 8 h post-hCG, respectively. In cultured COCs, FSH/forskolin induced Areg mRNA within 0.5 h that peaked at 4 h, a process blocked by inhibitors of p38MAPK (SB203580), MEK1 (PD98059) and PTGS2 (NS398) but not PKA (KT5720). Conversely, AREG but not FSH induced Ptsg2 mRNA at 0.5 h with peak expression of Ptgs2 and Areg mRNAs at 4 h, processes blocked by the EGF receptor tyrosine kinase inhibitor AG1478, PD98059 and NS398. PGE2 reversed the inhibitory effects of AG1478 on AREG induced expression of Areg but not Ptgs2, placing Ptgs2 downstream of EGF-R signaling. PMA and adenovirally expressed PGRA synergistically induced Areg mRNA in granulosa cells. In COCs AREG not only induced genes that impact matrix formation but also genes involved in steroidogenesis (StAR, Cyp11a1) and immune cell-like functions (Pdcd1, Runx1, Cd52). Collectively, FSH mediated induction of Areg mRNA via p38MAPK precedes AREG induction of Ptgs2 mRNA via ERK1/2. PGs acting via PTGER2 in cumulus cells provide a secondary, autocrine pathway to regulate expression of Areg in COCs showing critical functional links between G-protein coupled receptor and growth factor receptor pathways in ovulating follicles.
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