Academic Journal
Dysregulation of FGFR signalling by a selective inhibitor reduces germ cell survival in human fetal gonads of both sexes and alters the somatic niche in fetal testes
| العنوان: | Dysregulation of FGFR signalling by a selective inhibitor reduces germ cell survival in human fetal gonads of both sexes and alters the somatic niche in fetal testes |
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| المؤلفون: | Harpelunde Poulsen, K, Nielsen, J E, Frederiksen, H, Melau, C, Juul Hare, K, Langhoff Thuesen, L, Perlman, S, Lundvall, L, Mitchell, R T, Juul, A, Rajpert-De Meyts, E, Jørgensen, A |
| المصدر: | Harpelunde Poulsen , K , Nielsen , J E , Frederiksen , H , Melau , C , Juul Hare , K , Langhoff Thuesen , L , Perlman , S , Lundvall , L , Mitchell , R T , Juul , A , Rajpert-De Meyts , E & Jørgensen , A 2019 , ' Dysregulation of FGFR signalling by a selective inhibitor reduces germ cell survival in human fetal gonads of both sexes and alters the somatic niche in fetal testes ' , Human Reproduction , vol. 34 , no. 11 , pp. 2228-2243 . https://doi.org/10.1093/humrep/dez191 |
| سنة النشر: | 2019 |
| المجموعة: | University of Copenhagen: Research / Forskning ved Københavns Universitet |
| الوصف: | STUDY QUESTION: Does experimental manipulation of fibroblast growth factor 9 (FGF9)-signalling in human fetal gonads alter sex-specific gonadal differentiation? SUMMARY ANSWER: Inhibition of FGFR signalling following SU5402 treatment impaired germ cell survival in both sexes and severely altered the developing somatic niche in testes, while stimulation of FGF9 signalling promoted Sertoli cell proliferation in testes and inhibited meiotic entry of germ cells in ovaries. WHAT IS KNOWN ALREADY: Sex-specific differentiation of bipotential gonads involves a complex signalling cascade that includes a combination of factors promoting either testicular or ovarian differentiation and inhibition of the opposing pathway. In mice, FGF9/FGFR2 signalling has been shown to promote testicular differentiation and antagonize the female developmental pathway through inhibition of WNT4. STUDY DESIGN, SIZE, DURATION: FGF signalling was manipulated in human fetal gonads in an established ex vivo culture model by treatments with recombinant FGF9 (25 ng/ml) and the tyrosine kinase inhibitor SU5402 (10 μM) that was used to inhibit FGFR signalling. Human fetal testis and ovary tissues were cultured for 14 days and effects on gonadal development and expression of cell lineage markers were determined. PARTICIPANTS/MATERIALS, SETTING, METHODS: Gonadal tissues from 44 male and 33 female embryos/fetuses from first trimester were used for ex vivo culture experiments. Tissues were analyzed by evaluation of histology and immunohistochemical analysis of markers for germ cells, somatic cells, proliferation and apoptosis. Culture media were collected throughout the experimental period and production of steroid hormone metabolites was analyzed in media from fetal testis cultures by liquid chromatography-tandem mass spectrometry (LC-MS/MS). MAIN RESULTS AND THE ROLE OF CHANCE: Treatment with SU5402 resulted in near complete loss of gonocytes (224 vs. 14 OCT4+ cells per mm2, P < 0.05) and oogonia (1456 vs. 28 OCT4+ cells per mm2, P < 0.001) in ... |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| DOI: | 10.1093/humrep/dez191 |
| الاتاحة: | https://researchprofiles.ku.dk/da/publications/dysregulation-of-fgfr-signalling-by-a-selective-inhibitor-reduces-germ-cell-survival-in-human-fetal-gonads-of-both-sexes-and-alters-the-somatic-niche-in-fetal-testes(69a811e8-2d55-410e-b600-433152c7fafd).html https://doi.org/10.1093/humrep/dez191 https://curis.ku.dk/ws/files/237708278/dez191.pdf |
| Rights: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.88A331F9 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1093/humrep/dez191 |
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