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

Cecilia Garcia-Rudaz, Mauricio Dorfman, Srinivasa Nagalla, Konstantin Svechnikov, Olle Söder, Sergio Ojeda, Gregory Dissen

    Research output: Contribution to journalArticle

    8 Citations (Scopus)

    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.

    Original languageEnglish (US)
    Pages (from-to)319-331
    Number of pages13
    JournalReproduction
    Volume142
    Issue number2
    DOIs
    StatePublished - Aug 2011

    Fingerprint

    Stathmin
    Granulosa Cells
    Nerve Growth Factor
    Ovary
    Tumor Necrosis Factor-alpha
    Apoptosis
    Testosterone
    Cell Death
    17-alpha-Hydroxyprogesterone
    Tumor Necrosis Factor Receptors
    Receptor Protein-Tyrosine Kinases
    Enzymes
    Gonadotropins
    Proteomics
    Serine
    Cysts
    Estradiol
    Gene Expression
    Growth
    Proteins

    ASJC Scopus subject areas

    • Obstetrics and Gynecology
    • Reproductive Medicine
    • Embryology
    • Endocrinology
    • Cell Biology

    Cite this

    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. / Garcia-Rudaz, Cecilia; Dorfman, Mauricio; Nagalla, Srinivasa; Svechnikov, Konstantin; Söder, Olle; Ojeda, Sergio; Dissen, Gregory.

    In: Reproduction, Vol. 142, No. 2, 08.2011, p. 319-331.

    Research output: Contribution to journalArticle

    Garcia-Rudaz, Cecilia ; Dorfman, Mauricio ; Nagalla, Srinivasa ; Svechnikov, Konstantin ; Söder, Olle ; Ojeda, Sergio ; Dissen, Gregory. / 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. In: Reproduction. 2011 ; Vol. 142, No. 2. pp. 319-331.
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    AU - Nagalla, Srinivasa

    AU - Svechnikov, Konstantin

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    AU - Ojeda, Sergio

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    AB - 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.

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