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

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 p130(Cas), 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.