Spz1, a previously identified basic helix-loop-helix-leucine zipper (bHLH-Zip) transcription factor, is expressed specifically in the testis and epididymis of adult mice. However, Spz1's in vivo function is unclear. To study the function of Spz1 in vivo, we established Spz1 transgenic mice. Using this model, we were able to demonstrate that overexpression of Spz1 in the testis destroys tissue homeostasis at an early stage of spermatogenesis, which in turn induces apoptosis in germ cells and thus reduces male fertility. We identified that Spz1 is ectopically expressed in multiple tissues of transgenic male mice by Western blot analysis. In the testes of transgenic mice, Spz1 proteins were found to be overexpressed in both germ and somatic cells as determined by immunofluorescence staining. This upregulated cell proliferation was confirmed by in vivo BrdU incorporation in multinucleated gonocytes of 1-week-old transgenic mice. However, histological and immunohistochemical analyses indicated that these multinucleated germ cells in seminiferous tubules subsequently underwent apoptosis at 2 and 4 weeks of age through Fas/FasL- and ER stress-signaling pathways. Furthermore, germ cells surviving two cycles of meiosis suffered aberrant spermiogenesis, generating a large pool of abnormal spermatozoa. The transgenic male mice with reduced populations of normal spermatozoa produced offsprings of smaller litter sizes and became infertile at 6 months of age. These results suggest that cell proliferation in early spermatogenesis is critically regulated by multisignal pathways and unregulated cell proliferation at this stage, as induced by Spz1, leads to germ cell apoptosis. These results imply that Spz1 plays an important regulatory role during spermatogenesis.
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