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Oncotarget: Wnt signalling perturbs spermatogenesis


Here is a link to a video interview with Dr. Pradeep S. Tanwar about this research on the Oncotarget YouTube Channel

Oncotarget published "Germ cell-specific sustained activation of Wnt signalling perturbs spermatogenesis in aged mice, possibly through non-coding RNAs" which reported that the role of Wnt signalling in male germ cells remains poorly understood.

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 the mutant group.

Overactivation of Wnt/βcatenin signalling in a spermatogonial cell line resulted in reduced cell proliferation, viability and colony formation.

In summary, the results of this Oncotarget study highlight the significance of Wnt signalling in male germ cells.

Dr. Pradeep S. Tanwar from The University of Newcastle said, "Spermatogonial stem cells (SSCs) sustain spermatogenesis throughout the life of a male by self-renewal and differentiation to committed progenitors."

In seminiferous tubules, germ cells are organised in a highly orderly fashion where undifferentiated germ cells are located at the periphery close to the basement membrane in the basal compartment and the differentiated germ cells are situated towards the lumen in the adluminal compartment.

Precisely balanced germ cell proliferation and differentiation is essential for the maintenance of homeostasis between different germ cell populations and any disruptions result in fertility defects and/or testicular cancer.

Figure 10: Altered expression of non-coding RNAs in mutant testes. A. Heat-map from RNA sequencing of whole testes of control and mutant mice. The log2 FPKM (Fragments Per Kilobase of transcript per Million mapped reads) values for 104 genes are used for generation of the heat map in two groups. The colours correspond to the log2 of FPKM values, ranging from bright brown (2.5) to white (zero). Solid arrowhead marks genes that are turned off in mutant condition while empty arrowhead marks genes turned on in mutant condition. B. Graphical representation of the genes showing at least two-fold change in mutant testes. C. Putative structure of a novel non-coding RNA switched on in mutant mouse testes. D. Four fold up-regulation of expression of the novel non-coding RNA in the mutant testis using qRT-PCR analysis. Data is presented as means ± SEM (N=3/each).

Wnt signalling is essential for the development of primordial germ cells, which is the most primitive germ cell population.

Using RNA and protein analysis, spermatgonial cell culture, thymidine analogues labelling, flow sorting, and a genetically modified mouse model, they have shown that overactivation of Wnt signalling in germ cells causes defects in proliferation and differentiation leading to premature loss of germ cells.

Thus, this study has deciphered the precise role of Wnt signalling in germ cell development and differentiation.

The Tanwar Research Team concluded in their Oncotarget Research Paper, "our work using in vitro and in vivo model systems showed that aberrations in Wnt signalling leads to defective spermatogenesis primarily due to the abnormalities in meiotically committed germ cells. As abnormal Wnt signalling is associated with human male infertility and testicular cancer, it is likely that similar mechanisms might be operational in human patients."

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DOI - https://doi.org/10.18632/oncotarget.13920

Full text - https://www.oncotarget.com/article/13920/text/

Correspondence to - Pradeep S. Tanwar - pradeep.tanwar@newcastle.edu.au

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

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