Neurotrophins acting via TRKB receptors activate the JAGGED1-NOTCH2 cell-cell communication pathway to facilitate early ovarian development

Mauricio D. Dorfman, Bredford Kerr, Cecilia Garcia-Rudaz, Alfonso H. Paredes, Gregory Dissen, Sergio Ojeda

    Research output: Contribution to journalArticle

    13 Citations (Scopus)

    Abstract

    Tropomyosin-related kinase (TRK) receptor B (TRKB) mediates the supportive actions of neurotrophin 4/5 and brain-derived neurotrophic factor on early ovarian follicle development. Absence of TRKB receptors reduces granulosa cell (GC) proliferation and delays follicle growth. In the present study, we offer mechanistic insights into this phenomenon. DNA array and quantitative PCR analysis of ovaries from TrkB-null mice revealed that by the end of the first week of postnatal life, Jagged1, Hes1, and Hey2 mRNA abundance is reduced in the absence of TRKB receptors. Although Jagged1 encodes a NOTCH receptor ligand, Hes1 and Hey2 are downstream targets of the JAGGED1-NOTCH2 signaling system. Jagged1 is predominantly expressed in oocytes, and the abundance of JAGGED1 is decreased in TrkB -/- oocytes. Lack of TRKB receptors also resulted in reduced expression of c-Myc, a NOTCH target gene that promotes entry into the cell cycle, but did not alter the expression of genes encoding core regulators of cell-cycle progression. Selective restoration of JAGGED1 synthesis in oocytes of TrkB -/- ovaries via lentiviral-mediated transfer of the Jagged1 gene under the control of the growth differentiation factor 9 (Gdf9) promoter rescued c-Myc expression, GC proliferation, and follicle growth. 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.

    Original languageEnglish (US)
    Pages (from-to)5005-5016
    Number of pages12
    JournalEndocrinology
    Volume152
    Issue number12
    DOIs
    StatePublished - Dec 2011

    Fingerprint

    Granulosa Cells
    Nerve Growth Factors
    Cell Communication
    Oocytes
    Cell Proliferation
    Ovary
    Cell Cycle
    Growth Differentiation Factor 9
    Growth
    Ovarian Follicle
    Brain-Derived Neurotrophic Factor
    Oligonucleotide Array Sequence Analysis
    Genes
    Ligands
    Gene Expression
    Polymerase Chain Reaction
    Messenger RNA

    ASJC Scopus subject areas

    • Endocrinology

    Cite this

    Neurotrophins acting via TRKB receptors activate the JAGGED1-NOTCH2 cell-cell communication pathway to facilitate early ovarian development. / Dorfman, Mauricio D.; Kerr, Bredford; Garcia-Rudaz, Cecilia; Paredes, Alfonso H.; Dissen, Gregory; Ojeda, Sergio.

    In: Endocrinology, Vol. 152, No. 12, 12.2011, p. 5005-5016.

    Research output: Contribution to journalArticle

    Dorfman, Mauricio D. ; Kerr, Bredford ; Garcia-Rudaz, Cecilia ; Paredes, Alfonso H. ; Dissen, Gregory ; Ojeda, Sergio. / Neurotrophins acting via TRKB receptors activate the JAGGED1-NOTCH2 cell-cell communication pathway to facilitate early ovarian development. In: Endocrinology. 2011 ; Vol. 152, No. 12. pp. 5005-5016.
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