title: Targeted disruption of Nphp1 causes male infertility due to defects in the later steps of sperm morphogenesis in mice.
abstract: 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.
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Si-Tse
authors.initials: ST
authors.lastname: Jiang
authors.forename: Yuan-Yow
authors.initials: YY
authors.lastname: Chiou
authors.forename: Ellian
authors.initials: E
authors.lastname: Wang
authors.forename: Hsiu-Kuan
authors.initials: HK
authors.lastname: Lin
authors.forename: Sue-Ping
authors.initials: SP
authors.lastname: Lee
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Lu
authors.forename: Chi-Kuang Leo
authors.initials: CK
authors.lastname: Wang
authors.forename: Ming-Jer
authors.initials: MJ
authors.lastname: Tang
authors.forename: Hung
authors.initials: H
authors.lastname: Li
mesh_terms: D000199:Actins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001835:Body Weight; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D003598:Cytoskeletal Proteins; D005260:Female; D018507:Gene Expression Regulation, Developmental; D007248:Infertility, Male / Q000235:genetics*; D007674:Kidney Diseases / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009929:Organ Size; D010641:Phenotype; D012671:Seminiferous Tubules / Q000648:ultrastructure; D013076:Sperm Count; D013091:Spermatogenesis / Q000235:genetics*; D013094:Spermatozoa / Q000000981:diagnostic imaging / Q000254:growth & development* / Q000648:ultrastructure; D014463:Ultrasonography
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C534985:Nphp1 protein, mouse