CHES-1-like, the ortholog of a non-obstructive azoospermia-associated gene, blocks germline stem cell differentiation by upregulating Dpp expression in Drosophila testis
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Jun Yu1,3, Yujuan Liu1,3, Xiang Lan2, Hao Wu1,3, Yang Wen1, Zuomin Zhou1,3, Zhibin Hu1, Jiahao Sha1,3, Xuejiang Guo1,3,4, Chao Tong2
1State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China
2Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou 310058, China
3Department of Histology and Embryology, Nanjing Medical University, Nanjing 211166, China
4Animal Core Facility, Nanjing Medical University, Nanjing 211166, China
Chao Tong, email: firstname.lastname@example.org
Xuejiang Guo, email: email@example.com
Keywords: non-obstructive azoospermia, Drosophila, testis tumor, BMP signaling, germline stem cells
Received: February 22, 2016 Accepted: May 16, 2016 Published: June 2, 2016
Azoospermia is a high risk factor for testicular germ cell tumors, whose underlying molecular mechanisms remain unknown. In a genome-wide association study to identify novel loci associated with human non-obstructive azoospermia (NOA), we uncovered a single nucleotide polymorphism (rs1887102, P=2.60 ×10-7) in a human gene FOXN3. FOXN3 is an evolutionarily conserved gene. We used Drosophila melanogaster as a model system to test whether CHES-1-like, the Drosophila FOXN3 ortholog, is required for male fertility. CHES-1-like knockout flies are viable and fertile, and show no defects in spermatogenesis. However, ectopic expression of CHES-1-like in germ cells significantly reduced male fertility. With CHES-1-like overexpression, spermatogonia fail to differentiate after four rounds of mitotic division, but continue to divide to form tumor like structures. In these testes, expression levels of differentiation factor, Bam, were reduced, but the expression region of Bam was expanded. Further reduced Bam expression in CHES-1-like expressing testes exhibited enhanced tumor-like structure formation. The expression of daughters against dpp (dad), a downstream gene of dpp signaling, was upregulated by CHES-1-like expression in testes. We found that CHES-1-like could directly bind to the dpp promoter. We propose a model that CHES-1-like overexpression in germ cells activates dpp expression, inhibits spermatocyte differentiation, and finally leads to germ cell tumors.
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