WWC2 expression in the testis: Implications for spermatogenesis and male fertility.
Verena HöffkenSara Di PersioSandra LaurentinoMargot J WyrwollNicole TerwortAnke HermannAlbrecht RöpkeManon S OudJoachim WistubaSabine KlieschHermann J PavenstädtFrank TüttelmannNina NeuhausJoachim KremerskothenPublished in: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (2023)
The family of WWC proteins is known to regulate cell proliferation and organ growth control via the Hippo signaling pathway. As WWC proteins share a similar domain structure and a common set of interacting proteins, they are supposed to fulfill compensatory functions in cells and tissues. While all three WWC family members WWC1, WWC2, and WWC3 are found co-expressed in most human organs including lung, brain, kidney, and liver, in the testis only WWC2 displays a relatively high expression. In this study, we investigated the testicular WWC2 expression in spermatogenesis and male fertility. We show that the Wwc2 mRNA expression level in mouse testes is increased during development in parallel with germ cell proliferation and differentiation. The cellular expression of each individual WWC family member was evaluated in published single-cell mRNA datasets of murine and human testes demonstrating a high WWC2 expression predominantly in early spermatocytes. In line with this, immunohistochemistry revealed cytosolic WWC2 protein expression in primary spermatocytes from human testes displaying full spermatogenesis. In accordance with these findings, markedly lower WWC2 expression levels were detected in testicular tissues from mice and men lacking germ cells. Finally, analysis of whole-exome sequencing data of male patients affected by infertility and unexplained severe spermatogenic failure revealed several heterozygous, rare WWC2 gene variants with a proposed damaging function and putative impact on WWC2 protein structure. Taken together, our findings provide novel insights into the testicular expression of WWC2 and show its cell-specific expression in spermatocytes. As rare WWC2 variants were identified in the background of disturbed spermatogenesis, WWC2 may be a novel candidate gene for male infertility.
Keyphrases
- poor prognosis
- cell proliferation
- single cell
- binding protein
- endothelial cells
- signaling pathway
- type diabetes
- gene expression
- induced apoptosis
- stem cells
- copy number
- pi k akt
- long non coding rna
- brain injury
- adipose tissue
- dna methylation
- cell death
- randomized controlled trial
- cell cycle
- end stage renal disease
- induced pluripotent stem cells
- insulin resistance
- bone marrow
- metabolic syndrome
- mass spectrometry
- artificial intelligence
- african american
- transcription factor
- cell cycle arrest
- patient reported outcomes
- high resolution
- single molecule
- skeletal muscle
- subarachnoid hemorrhage
- embryonic stem cells