CHES-1-like, the ortholog of a non-obstructive azoospermia-associated gene, blocks germline stem cell differentiation by upregulating Dpp expression in Drosophila testis.
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.
State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China.|Department of Histology and Embryology, Nanjing Medical University, Nanjing 211166, China.
Jun
J
Yu
State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China.|Department of Histology and Embryology, Nanjing Medical University, Nanjing 211166, China.
Yujuan
Y
Liu
Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou 310058, China.
Xiang
X
Lan
State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China.|Department of Histology and Embryology, Nanjing Medical University, Nanjing 211166, China.
Hao
H
Wu
State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China.
Yang
Y
Wen
State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China.|Department of Histology and Embryology, Nanjing Medical University, Nanjing 211166, China.
Zuomin
Z
Zhou
State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China.
Zhibin
Z
Hu
State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China.|Department of Histology and Embryology, Nanjing Medical University, Nanjing 211166, China.
Jiahao
J
Sha
State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China.|Department of Histology and Embryology, Nanjing Medical University, Nanjing 211166, China.|Animal Core Facility, Nanjing Medical University, Nanjing 211166, China.
Xuejiang
X
Guo
Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou 310058, China.
Chao
C
Tong
D000483:Alleles; D000818:Animals; D053713:Azoospermia / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D000072669:Gene Editing; D005854:Germ Cells / Q000166:cytology; D008297:Male; D009373:Neoplasms, Germ Cell and Embryonal / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D013091:Spermatogenesis; D013737:Testis / Q000378:metabolism* / Q000473:pathology; D019076:Transgenes; D015854:Up-Regulation
C575451:CHES-1-like protein, Drosophila; D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D051858:Forkhead Transcription Factors; C091674:bam protein, Drosophila; C064196:dpp protein, Drosophila
BMP signaling; Drosophila; germline stem cells; non-obstructive azoospermia; testis tumor