title: Excessive ovarian production of nerve growth factor elicits granulosa cell apoptosis by setting in motion a tumor necrosis factor α/stathmin-mediated death signaling pathway.
abstract: Excessive nerve growth factor (NGF) production by the ovary, achieved via a transgenic approach, results in arrested antral follicle growth, reduced ovulatory capacity, and a predisposition to cyst formation in response to mildly elevated LH levels. Two salient features in these mutant mice (termed 17NF) are an elevated production of 17α-hydroxyprogesterone (17-OHP(4)), testosterone, and estradiol (E(2)) in response to gonadotropins, and an increased frequency of granulosa cell (GC) apoptosis. In this study, we show that the increase in steroidal response is associated with enhanced expression of Cyp17a1, Hsd17b, and Cyp19a1, which encode the enzymes catalyzing the synthesis of 17-OHP(4), testosterone, and E(2) respectively. Using a proteomic approach, we identified stathmin (STMN1), as a protein that is overproduced in 17NF ovaries. In its phosphorylated state, STMN1 mediates a cell death signal initiated by tumor necrosis factor α (TNF). STMN1 is expressed in GCs and excessive NGF increases its abundance as well as that of its forms phosphorylated at serine (Ser) 16, 25, and 38. TNF synthesis is also increased in 17NF ovaries, and this change is abolished by blocking neurotrophic tyrosine kinase receptors. Inhibiting TNF actions in vivo by administering a soluble TNF receptor prevented the increase in total and phosphorylated STMN1 production, as well as GC apoptosis in NGF-overproducing ovaries. These results indicate that an excess of NGF in the ovary promotes steroidogenesis by enhancing the expression of enzyme genes involved in 17-OHP(4), testosterone, and E(2) synthesis, and causes GC apoptosis by activating a TNF/ STMN1-mediated cell death pathway.
authors.affiliation: Division of Neuroscience, Oregon National Primate Research Center-Oregon Health and Science University, Beaverton, Oregon 97006, USA.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Garcia-Rudaz
authors.forename: Mauricio
authors.initials: M
authors.lastname: Dorfman
authors.forename: Srinivasa
authors.initials: S
authors.lastname: Nagalla
authors.forename: Konstantin
authors.initials: K
authors.lastname: Svechnikov
authors.forename: Olle
authors.initials: O
authors.lastname: Söder
authors.forename: Sergio R
authors.initials: SR
authors.lastname: Ojeda
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Dissen
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001141:Aromatase / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D012739:Gonadal Steroid Hormones / Q000378:metabolism; D006062:Gonadotropins / Q000494:pharmacology; D006107:Granulosa Cells / Q000378:metabolism*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D010053:Ovary / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D050777:Stathmin / Q000235:genetics / Q000378:metabolism*; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D012739:Gonadal Steroid Hormones; D006062:Gonadotropins; D007527:Isoenzymes; D012333:RNA, Messenger; D050777:Stathmin; C493994:Stmn1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D020932:Nerve Growth Factor; D015067:17-Hydroxysteroid Dehydrogenases; D001141:Aromatase; D013254:Steroid 17-alpha-Hydroxylase