Impaired spermatogenesis and male fertility defects in CIZ/Nmp4‐disrupted mice

• Published in: Genes to cells : devoted to molecular & cellular mechanisms 2004-06, Vol.9 (6), p.575-589
• Main Authors: Nakamoto, Tetsuya, Shiratsuchi, Akiko, Oda, Hideaki, Inoue, Keiichi, Matsumura, Tomoko, Ichikawa, Motoshi, Saito, Toshiki, Seo, Sachiko, Maki, Kazuhiro, Asai, Takashi, Suzuki, Takahiro, Hangaishi, Akira, Yamagata, Tetsuya, Aizawa, Shinichi, Noda, Masaki, Nakanishi, Yoshinobu, Hirai, Hisamaru
• Format: Article
• Language: English
• Subjects: Aging; Alleles; Animals; beta-Galactosidase; Body Size - genetics; Cells, Cultured; DNA-Binding Proteins - metabolism; Drug Resistance - genetics; Exons; Gene Expression; Genome; Infertility, Male - pathology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neomycin; Nuclear Matrix-Associated Proteins - metabolism; Nuclear Matrix-Associated Proteins - physiology; Precipitin Tests; Smad Proteins; Smad1 Protein; Spermatogenesis; Stem Cells - cytology; Testis - pathology; Trans-Activators - metabolism; Trans-Activators - physiology; Transcription Factors - metabolism; Transcription Factors - physiology; Zinc Fingers - physiology
• ISSN: 1356-9597; 1365-2443
• DOI: 10.1111/j.1356-9597.2004.00746.x

CIZ (Cas interacting zinc finger protein), also called Nmp4 (nuclear matrix protein 4), is a nucleo‐cytoplasmic shuttling transcription factor that regulates the expression of collagen and matrix metalloproteinases. CIZ/Nmp4 was originally cloned by its binding to p130Cas, a focal adhesion protein, and was recently shown to suppress BMP2 (bone mophogenetic protein 2) signalling. To explore the physiological role of CIZ/Nmp4, we disrupted CIZ/Nmp4‐gene by inserting beta‐galactosidase and neomycin resistance genes into the 2nd exon of CIZ/Nmp4‐gene, which is utilized by all the sequenced alternative forms. CIZ−/− mice were born and grew to adulthood. Although they tend to be smaller than wild‐type mice, no pathological abnormality was observed except in the testis. Histological analysis of the testes revealed variable degrees of spermatogenic cell degeneration within the seminiferous tubules of CIZ−/− mice, resembling the histology of the ‘Germinal‐cell aplasia with focal spermatogenesis’. Some of the CIZ−/− male mice developed infertility. TUNEL assay on testis sections revealed an increased occurrence of apoptosis of spermatogenic cells in the testes of CIZ−/− mice. CIZ/Nmp4 was co‐localized with Smad1 in the testis, suggesting that a disregulation of BMP signalling could cause these phenotypes. These results suggest that CIZ/Nmp4 plays roles in the progress and the maintenance of spermatogenesis.