Analysisof CIZ disrupted mice

CIZ（Cas interactig zinc finger protein，Cas相互作用锌指蛋白），又称核基质蛋白4（nuclear matrix protein 4，Nmp 4），是一种核质穿梭转录因子，调节胶原蛋白和基质金属蛋白酶的表达。CIZ/Nmp 4最初是通过与黏着斑蛋白p130 α结合而克隆<cus>的，最近显示其抑制BMP 2（骨形态发生蛋白2）信号传导。为了探索CIZ/Nmp 4的生理作用，我们通过将β-半乳糖苷酶和新霉素抗性基因插入CIZ<nd>/Nmp 4-基因的第2^外显子来破坏CIZ/Nmp 4-基因，这被所有测序的替代形式所利用。CIZ^&lt;-/-&gt;小鼠出生并生长至成年。虽然它们往往比野生型小鼠小，但除睾丸外未观察到病理异常。睾丸的组织学分析揭示了CIZ^&lt;-/-&gt;小鼠的曲细精管内不同程度的生精细胞变性，类似于具有局灶性精子发生的生殖细胞发育不全的组织学。一些CIZ^&lt;-/-&gt;雄性小鼠发展为不育。睾丸切片上的TUNEL测定揭示CIZ^&lt;-/-&gt;小鼠睾丸中生精细胞三元共聚物的发生增加。CIZ/Nmp 4与Smad 1在睾丸中共定位，表明BMP信号传导的失调可能导致这些表型。这些结果表明CIZ/Nmp 4在精子发生的进程和维持中起作用。

CIZ(Cas interactig zinc finger protein), also called Nmp4 (nuclear matrix protein 4), is a nucleo-cytoplasic shuttling transcription factor that regulates the expression of collagen and matrix metalloproteinases. CIZ/Nmp4 was originally cloned by its binding to p130^<cus>, a focal adhesion protein, and was recently shown to suppress BMP2 (bone mophogenetic protein 2) signaling. To explore the physiological role of CIZ/Nmp4, we disrupted CIZ/Nmp4-gene by inserting beta-galactosidase and neomycin resistance genes into the 2^<nd> 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 poptosis of spermatogenic cells in the testes of CIZ^<-/-> mice. CIZ/Nmp4 was colocalized with Smadl in the testis, suggesting that a disregulation of BMP signaling could cause these phenotypes. These results suggest that CIZ/Nmp4 plays roles in the progress and the maintenance of spermatogenesis.