NEURAL CONTROL OF THE PREPUBERTAL OVARY

Summary

Principal Investigator: Sergio Ojeda
Affiliation: Oregon Health and Science University
Country: USA
Abstract: DESCRIPTION: (Adapted from the applicant's abstract) This is a renewal application aimed at elucidating some of the basic neuroendocrine and cellular mechanisms overning mammalian ovarian development. During the last period of support we employed a combination of cellular, molecular and genetic approaches to demonstrate the existence of a neurotrophin-mediated regulatory system that is acting at the interface between the endocrine and nervous systems -- contributes to the developmental control of ovarian function. In related studies, we identified a series of additional genes that may belong to the hierarchy of regulatory molecules controlling ovarian folliculogenesis, follicular growth and ovulation. The recognition of these new regulatory components, and the use of genetic approaches to modify the expression of genes in a cell-specific and temporally restricted manner, provides us with a new opportunity to unravel some of the key cell-cell regulatory mechanisms underlying mammalian ovarian development. To initiate this undertaking we propose two sets of studies: The first, to define the physiological importance of NGF and its receptors I follicular growth and ovulation, and their contribution to the etiology of ovarian cystic disease; the other, to elucidate the role that a set of functionally diverse genes found to be differentially expressed in the ovary at two key developmental phases (folliculogenesis and first ovulation) may play in the regulation of these processes. To this end, the following specific aims are proposed: 1. To test the hypothesis that, while required for normal follicular growth, NGF overproduction in endocrine cells of the follicular wall leads to the development of cystic ovarian disease via activation of the low-affinity neurotrophin receptor, p75NGFR. 2. To examine the hypothesis that activation of trkA, the high ffinity tyrosine kinase NGF receptor, in ovarian endocrine cells of mesenchymal origin contributes to the completion of two critical phases in the natural history of the developing ovary, the initiation of preantral follicular development and rupture of the follicular wall at ovulation. 3. To define the role that insulin receptor-related receptor (IRR), an orphan receptor of the insulin receptor family recently found to be co-expressed with trkA in thecal cells of periovulatory follicles, plays in ovulation, and to molecularly identify the gene encoding the IRR ligand. 4. To test the hypothesis that follicular formation requires the temporal and cell-specific coordinated expression of three functionally diverse genes found to be differentially displayed at the time of folliculogenesis; the adhesion molecule Cadherin-11, the protooncogene PTTG, and the transcriptional regulator ENX-1.
Funding Period: 1988-02-01 - 2007-03-31
more information: NIH RePORT

Top Publications

  1. pmc Targeted gene silencing to induce permanent sterility
    G A Dissen
    Division of Neuroscience, Oregon National Primate Research Center Oregon Health and Science University, Beaverton, OR 97006 3448, USA
    Reprod Domest Anim 47:228-32. 2012
  2. pmc Hypothalamic EAP1 (enhanced at puberty 1) is required for menstrual cyclicity in nonhuman primates
    Gregory A Dissen
    Division of Neuroscience, Oregon National Primate Research Center, 505 North West 185th Avenue, Beaverton, Oregon 97006 3448, USA
    Endocrinology 153:350-61. 2012
  3. pmc Neurotrophins acting via TRKB receptors activate the JAGGED1-NOTCH2 cell-cell communication pathway to facilitate early ovarian development
    Mauricio D Dorfman
    Division of Neuroscience, Oregon National Primate Research Center Oregon Health and Science University, 505 Northwest 185th Avenue, Beaverton, Oregon 97006, USA
    Endocrinology 152:5005-16. 2011
  4. pmc 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
    Division of Neuroscience, Oregon National Primate Research Center Oregon Health and Science University, Beaverton, Oregon 97006, USA
    Reproduction 142:319-31. 2011
  5. pmc Oxytocin receptors in the primate ovary: molecular identity and link to apoptosis in human granulosa cells
    S Saller
    Anatomy and Cell Biology, University of Munich, Biedersteiner Strasse 29, 80802 Munchen, Germany
    Hum Reprod 25:969-76. 2010
  6. pmc In vivo manipulation of gene expression in non-human primates using lentiviral vectors as delivery vehicles
    Gregory A Dissen
    Division of Neuroscience, Oregon National Primate Research Center Oregon Health and Science University, Beaverton, OR 97006 3448, USA
    Methods 49:70-7. 2009
  7. pmc NTRK1 and NTRK2 receptors facilitate follicle assembly and early follicular development in the mouse ovary
    Bredford Kerr
    Division of Neuroscience, Oregon National Primate Research Center Oregon Health and Science University, 505 Northwest 185th Avenue, Beaverton, Oregon 97006, USA
    Reproduction 138:131-40. 2009
  8. pmc Excessive ovarian production of nerve growth factor facilitates development of cystic ovarian morphology in mice and is a feature of polycystic ovarian syndrome in humans
    Gregory A Dissen
    Division of Neuroscience, Oregon National Primate Research Center, Beaverton, Oregon 97006 3448, USA
    Endocrinology 150:2906-14. 2009
  9. pmc Role of neurotrophic factors in early ovarian development
    Gregory A Dissen
    Division of Neuroscience, Oregon National Primate Research Center Oregon Health and Science University, Beaverton, Oregon 97006 3448, USA
    Semin Reprod Med 27:24-31. 2009
  10. ncbi Fbxw15/Fbxo12J is an F-box protein-encoding gene selectively expressed in oocytes of the mouse ovary
    Elsa de la Chesnaye
    UIM en Biología del Desarrollo, Centro Medico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico
    Biol Reprod 78:714-25. 2008

Scientific Experts

  • Gregory A Dissen
  • W Dees
  • A Mayerhofer
  • Lars Kunz
  • Cecilia Garcia-Rudaz
  • Sergio R Ojeda
  • Bredford Kerr
  • Alfonso Paredes
  • Mauricio D Dorfman
  • Mauricio Dorfman
  • S Saller
  • Elsa de la Chesnaye
  • Manuel Ricu
  • S R Ojeda
  • Veronica Tapia
  • C Salas
  • Alfonso H Paredes
  • Konstantin Svechnikov
  • Srinivasa Nagalla
  • Olle Soder
  • U Berg
  • R Stouffer
  • D Berg
  • Juan Pablo Mendez
  • Horacio Merchant-Larios
  • Hernan E Lara
  • Monika Greiner
  • Lois Colgin
  • Felix Luna
  • Neil D Rawlings
  • Francesco Galimi
  • M Valladares
  • C Romero
  • R Pommer
  • C Mastronardi
  • H E Lara
  • M Julio-Pieper
  • M Vega
  • B Kerr
  • Maria E Costa
  • Anda Cornea

Detail Information

Publications18

  1. pmc Targeted gene silencing to induce permanent sterility
    G A Dissen
    Division of Neuroscience, Oregon National Primate Research Center Oregon Health and Science University, Beaverton, OR 97006 3448, USA
    Reprod Domest Anim 47:228-32. 2012
    ....
  2. pmc Hypothalamic EAP1 (enhanced at puberty 1) is required for menstrual cyclicity in nonhuman primates
    Gregory A Dissen
    Division of Neuroscience, Oregon National Primate Research Center, 505 North West 185th Avenue, Beaverton, Oregon 97006 3448, USA
    Endocrinology 153:350-61. 2012
    ....
  3. pmc Neurotrophins acting via TRKB receptors activate the JAGGED1-NOTCH2 cell-cell communication pathway to facilitate early ovarian development
    Mauricio D Dorfman
    Division of Neuroscience, Oregon National Primate Research Center Oregon Health and Science University, 505 Northwest 185th Avenue, Beaverton, Oregon 97006, USA
    Endocrinology 152:5005-16. 2011
    ..These results suggest that neurotrophins acting via TRKB receptors facilitate early follicle growth by supporting a JAGGED1-NOTCH2 oocyte-to-GC communication pathway, which promotes GC proliferation via a c-MYC-dependent mechanism...
  4. pmc 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
    Division of Neuroscience, Oregon National Primate Research Center Oregon Health and Science University, Beaverton, Oregon 97006, USA
    Reproduction 142:319-31. 2011
    ....
  5. pmc Oxytocin receptors in the primate ovary: molecular identity and link to apoptosis in human granulosa cells
    S Saller
    Anatomy and Cell Biology, University of Munich, Biedersteiner Strasse 29, 80802 Munchen, Germany
    Hum Reprod 25:969-76. 2010
    ..Human IVF-derived (h)GCs possess a functional OT receptor (OTR), linked to elevation of intracellular Ca(2+), but molecular identity of the receptor for OT in human granulosa cells (hGCs) and down-stream consequences are not known...
  6. pmc In vivo manipulation of gene expression in non-human primates using lentiviral vectors as delivery vehicles
    Gregory A Dissen
    Division of Neuroscience, Oregon National Primate Research Center Oregon Health and Science University, Beaverton, OR 97006 3448, USA
    Methods 49:70-7. 2009
    ..Finally, we describe in detail the lentiviral vector production protocol we use and provide examples of how the vector can be employed to target peripheral tissues and the brain...
  7. pmc NTRK1 and NTRK2 receptors facilitate follicle assembly and early follicular development in the mouse ovary
    Bredford Kerr
    Division of Neuroscience, Oregon National Primate Research Center Oregon Health and Science University, 505 Northwest 185th Avenue, Beaverton, Oregon 97006, USA
    Reproduction 138:131-40. 2009
    ..They also suggest that a mechanism by which NTRK2 receptors facilitate subsequent follicle development is by inducing the formation of functional FSHR...
  8. pmc Excessive ovarian production of nerve growth factor facilitates development of cystic ovarian morphology in mice and is a feature of polycystic ovarian syndrome in humans
    Gregory A Dissen
    Division of Neuroscience, Oregon National Primate Research Center, Beaverton, Oregon 97006 3448, USA
    Endocrinology 150:2906-14. 2009
    ....
  9. pmc Role of neurotrophic factors in early ovarian development
    Gregory A Dissen
    Division of Neuroscience, Oregon National Primate Research Center Oregon Health and Science University, Beaverton, Oregon 97006 3448, USA
    Semin Reprod Med 27:24-31. 2009
    ..Altogether, these observations indicate that NTs are important contributors to the gonadotropin-independent process underlying the formation and initiation of ovarian follicular growth...
  10. ncbi Fbxw15/Fbxo12J is an F-box protein-encoding gene selectively expressed in oocytes of the mouse ovary
    Elsa de la Chesnaye
    UIM en Biología del Desarrollo, Centro Medico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico
    Biol Reprod 78:714-25. 2008
    ..The specific expression of Fbxw15/Fbxp12J in oocytes and its developmental pattern of expression suggest a role for this gene in the regulation of oocyte physiology...
  11. pmc Functional development of the ovarian noradrenergic innervation
    Manuel Ricu
    Department of Biochemistry and Molecular Biology, Faculty of Chemistry and Pharmaceutical Sciences, Universidad de Chile, P O Box 233, Santiago 1 838 0492, Chile
    Endocrinology 149:50-6. 2008
    ..These results indicate that vesicular release of NE from ovarian noradrenergic nerves begins to operate by the third week of postnatal life, becoming fully functional near the time of puberty...
  12. ncbi Fxna, a novel gene differentially expressed in the rat ovary at the time of folliculogenesis, is required for normal ovarian histogenesis
    Cecilia Garcia-Rudaz
    Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, USA
    Development 134:945-57. 2007
    ..As an endoplasmic reticulum-bound peptidase, Fxna may facilitate follicular organization by processing precursor proteins required for intraovarian cell-to-cell communication...
  13. pmc FSH regulates acetycholine production by ovarian granulosa cells
    Artur Mayerhofer
    Anatomisches Institut der Universität München, Deutschland
    Reprod Biol Endocrinol 4:37. 2006
    ..To gain further insights into the possible role of ACh in the ovary, we examined ChAT expression in the gland before and after birth, as well as in adults, and studied the regulation of ACh production by FSH...
  14. ncbi Origin and ontogeny of mammalian ovarian neurons
    W Les Dees
    Department of Veterinary Integrative Biosciences, College of Veterinary Medicine, Texas A and M University, College Station, Texas 77845 4458, USA
    Endocrinology 147:3789-96. 2006
    ..Results demonstrate that p75NTR-expressing ovarian neurons originate from the neural crest and that a catecholaminergic subset is associated with pubertal maturation of the ovary and subsequent reproductive function...
  15. ncbi Nerve growth factor-dependent activation of trkA receptors in the human ovary results in synthesis of follicle-stimulating hormone receptors and estrogen secretion
    C Salas
    Laboratorio de Endocrinología y Biología Reproductiva, Departamento Obstetricia y Ginecología, Facultad de Medicina, Hospital Clínico J J Aguirre, Universidad de Chile, Santos Dumont 999 Independencia, Santiago 838 0456, Chile
    J Clin Endocrinol Metab 91:2396-403. 2006
    ..Previous studies showed that nerve growth factor (NGF) induces the expression of functional FSH receptors (FSHR) in preantral follicles of the developing rat ovary...
  16. ncbi Expression of the insulin receptor-related receptor is induced by the preovulatory surge of luteinizing hormone in thecal-interstitial cells of the rat ovary
    Gregory A Dissen
    Division of Neuroscience, Oregon Regional Primate Research Center, 505 N W 185th Avenue, Beaverton, Oregon 97006 3448, USA
    Endocrinology 147:155-65. 2006
    ....
  17. ncbi Loss of synaptonemal complex protein-1, a synaptonemal complex protein, contributes to the initiation of follicular assembly in the developing rat ovary
    Alfonso Paredes
    Division of Neuroscience, Oregon National Primate Research Center, Beaverton, 97006, USA
    Endocrinology 146:5267-77. 2005
    ..SCP1-deficient ovaries exhibited an increased number of newly formed follicles, suggesting that completion of meiotic prophase I endows oocytes with the ability to orchestrate follicular assembly...
  18. ncbi Voltage-dependent K+ channel acts as sex steroid sensor in endocrine cells of the human ovary
    Lars Kunz
    Anatomical Institute, University of Munich, Biedersteiner Str 29, Munich, Germany
    J Cell Physiol 206:167-74. 2006
    ..Our data might also be important for Kv4 channels in the brain and the cardiovascular system where rapid steroid effects are discussed in the context of prevention of cell death...