Oncotarget

Research Papers: Gerotarget (Focus on Aging):

Germ cell-specific sustained activation of Wnt signalling perturbs spermatogenesis in aged mice, possibly through non-coding RNAs

Manish Kumar, Joshua Atkins, Murray Cairns, Ayesha Ali and Pradeep S. Tanwar _

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Oncotarget. 2016; 7:85709-85727. https://doi.org/10.18632/oncotarget.13920

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Abstract

Manish Kumar1, Joshua Atkins1, Murray Cairns1, Ayesha Ali1 and Pradeep S. Tanwar1

1 School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, New South Wales, Australia

Correspondence to:

Pradeep S. Tanwar, email:

Keywords: Wnt, βcatenin, spermatgonia, testicular cancer, fertility, Gerotarget

Received: October 05, 2016 Accepted: December 06, 2016 Published: December 15, 2016

Abstract

Dysregulated Wnt signalling is associated with human infertility and testicular cancer. However, the role of Wnt signalling in male germ cells remains poorly understood. In this study, we first confirmed the activity of Wnt signalling in mouse, dog and human testes. To determine the physiological importance of the Wnt pathway, we developed a mouse model with germ cell-specific constitutive activation of βcatenin. In young mutants, similar to controls, germ cell development was normal. However, with age, mutant testes showed defective spermatogenesis, progressive germ cell loss, and flawed meiotic entry of spermatogonial cells. Flow sorting confirmed reduced germ cell populations at the leptotene/zygotene stages of meiosis in mutant group. Using thymidine analogues-based DNA double labelling technique, we further established decline in germ cell proliferation and differentiation. Overactivation of Wnt/βcatenin signalling in a spermatogonial cell line resulted in reduced cell proliferation, viability and colony formation. RNA sequencing analysis of testes revealed significant alterations in the non-coding regions of mutant mouse genome. One of the novel non-coding RNAs was switched on in mutant testes compared to controls. QPCR analysis confirmed upregulation of this unique non-coding RNA in mutant testis. In summary, our results highlight the significance of Wnt signalling in male germ cells.


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