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Activation of Notch Signaling by Oocytes and Jag1 in Mouse Ovarian Granulosa Cells.

ABSTRACT: The Notch pathway plays diverse and complex roles in cell signaling during development. In the mammalian ovary, Notch is important for the initial formation and growth of follicles, and for regulating the proliferation and differentiation of follicular granulosa cells during the periovulatory period. This study seeks to determine the contribution of female germ cells toward the initial activation and subsequent maintenance of Notch signaling within somatic granulosa cells of the ovary. To address this issue, transgenic Notch reporter (TNR) mice were crossed with Sohlh1-mCherry (S1CF) transgenic mice to visualize Notch-active cells (EGFP) and germ cells (mCherry) simultaneously in the neonatal ovary. To test the involvement of oocytes in activation of Notch signaling in ovarian somatic cells, we ablated germ cells using busulfan, a chemotherapeutic alkylating agent, or investigated KitWv/Wv (viable dominant white-spotting) mice that lack most germ cells. The data reveal that Notch pathway activation in granulosa cells is significantly suppressed when germ cells are reduced. We further demonstrate that disruption of the gene for the Notch ligand Jag1 in oocytes similarly impacts Notch activation and that recombinant JAG1 enhances Notch target gene expression in granulosa cells. These data are consistent with the hypothesis that germ cells provide a ligand, such as Jag1, that is necessary for activation of Notch signaling in the developing ovary.

SUBMITTER: Hubbard N

PROVIDER: S-EPMC6850001 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Project description:STUDY QUESTION:What is the X chromosomal content of oocytes and granulosa cells of primordial/primary (small) follicles and stromal cells in ovaries of young patients with Turner's syndrome (TS)? SUMMARY ANSWER:Small ovarian follicles were detected in one-half of the patients studied, and X chromosome analysis revealed that most oocytes were normal, granulosa cells were largely monosomic, while stromal cells showed a high level of mosaicism. WHAT IS KNOWN ALREADY:Most women with TS experience a premature reduction or complete loss of fertility due to an accelerated loss of gametes. To determine whether fertility preservation in this group of patients is feasible, there is a strong need for information on the X chromosomal content of ovarian follicular and stromal cells. STUDY DESIGN, SIZE, DURATION:Small follicles (<50 ?m) and stromal cells were isolated from ovarian tissue of young TS patients and analysed for their X chromosomal content. In addition to ovarian cells, several other cell types from the same patients were analysed. PARTICIPANTS/MATERIALS, SETTING, METHODS:After unilateral ovariectomy, ovarian cortex tissue was obtained from 10 TS patients (aged 2-18 years) with numerical abnormalities of the X chromosome. Ovarian cortex fragments were prepared and cryopreserved. One fragment from each patient was thawed and enzymatically digested to obtain stromal cells and primordial/primary follicles. Stromal cells, granulosa cells and oocytes were analysed by FISH using an X chromosome-specific probe. Extra-ovarian cells (lymphocytes, buccal cells and urine cells) of the same patients were also analysed by FISH. Ovarian tissue used as control was obtained from individuals undergoing oophorectomy as part of their gender affirming surgery. MAIN RESULTS AND THE ROLE OF CHANCE:Ovarian follicles were detected in 5 of the 10 patients studied. A method was developed to determine the X chromosomal content of meiosis I arrested oocytes from small follicles. This revealed that 42 of the 46 oocytes (91%) that were analysed had a normal X chromosomal content. Granulosa cells were largely 45,X but showed different levels of X chromosome mosaicism between patients and between follicles of the same patient. Despite the presence of a low percentage (10-45%) of 46,XX ovarian cortex stromal cells, normal macroscopic ovarian morphology was observed. The level of mosaicism in lymphocytes, buccal cells or urine-derived cells was not predictive for mosaicism in ovarian cells. LIMITATIONS, REASONS FOR CAUTION:The results are based on a small number (n =?5) of TS patient samples but provide evidence that the majority of oocytes have a normal X chromosomal content and that follicles from the same patient can differ with respect to the level of mosaicism of their granulosa cells. The functional consequences of these observations require further investigation. WIDER IMPLICATIONS OF THE FINDINGS:The results indicate that despite normal ovarian and follicular morphology, stromal cells and granulosa cells of small follicles in patients with TS may display a high level of mosaicism. Furthermore, the level of mosaicism in ovarian cells cannot be predicted from the analysis of extra-ovarian tissue. These findings should be considered by physicians when offering cryopreservation of ovarian tissue as an option for fertility preservation in young TS patients. STUDY FUNDING/COMPETING INTEREST(S):Unconditional funding was received from Merck B.V. The Netherlands (Number A16-1395) and the foundation 'Radboud Oncologie Fonds' (Number KUN 00007682). The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER:NCT03381300.

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Activation of Notch Signaling by Oocytes and Jag1 in Mouse Ovarian Granulosa Cells.

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