Human Molecular Genetics Advance Access originally published online on August 5, 2008
Human Molecular Genetics 2008 17(21):3368-3379; doi:10.1093/hmg/ddn231
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Targeted disruption of Nphp1 causes male infertility due to defects in the later steps of sperm morphogenesis in mice
1 Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan 2 Department of Pediatrics, Institute of Clinical Medicine 3 Department of Physiology, National Cheng Kung University Medical College, Tainan 704, Taiwan 4 Department of Life Sciences, National Taiwan Normal University, Taipei 106, Taiwan 5 National Laboratory Animal Center, National Applied Research Laboratories, Taipei 106, Taiwan 6 Institute of Biochemistry, National Yang-Ming University, Taipei 112, Taiwan
* To whom correspondence should be addressed at: Institute of Molecular Biology, Academia Sinica, Nankang, Taipei 11529, Taiwan. Tel: +886 227880460; Fax: +886 227826085; Email: hungli{at}ccvax.sinica.edu.tw
Received June 15, 2008; Accepted August 4, 2008
Juvenile nephronophthisis type I is the most common genetic disorder causing end-stage renal failure in children and young adults. The defective gene responsible has been identified as NPHP1. Its gene product, nephrocystin-1, is a novel protein of uncertain function that is widely expressed in many tissues and not just confined to the kidney. To gain insight into the physiological function of nephrocystin, Nphp1-targeted mutant mice were generated by homologous recombination. Interestingly, homozygous Nphp1 mutant mice were viable without renal manifestations of nephronophthisis. They appeared normal, but males were infertile with oligoteratozoospermia. Histological analysis of the seminiferous tubules showed that spermatogenesis was blocked at the early stages of spermatid elongation, with degenerating spermatids sloughing off into the lumen. Electron microscopic analysis revealed detachment of early elongating spermatids from Sertoli cells, and a failure of sperm head and tail morphogenesis. However, a few mature spermatozoa were still deposited in the epididymis, though they were frequently dead, immotile, or malformed. These novel findings indicate that nephrocystin is critically required for the differentiation of early elongating spermatids into spermatozoa in mice. The possible roles of nephrocystin in the formation and maintenance of Sertoli–spermatid junctions are still under investigation.
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