DAZAP1, an hnRNP protein, is required for normal growth and spermatogenesis in mice

Abstract

DAZAP1 (Deleted in Azoospermia Associated Protein 1) is a ubiquitous hnRNP protein that is expressed most abundantly in the testis. Its ability to shuttle between the nucleus and the cytoplasm and its exclusion from the transcriptionally inactive XY body in pachytene spermatocytes implicate it in mRNA transcription and transport. We generated Dazap1 mutant alleles to study the role of DAZAP1 in mouse development. Most mice homozygous for the null allele as well as a hypomorphic Fn allele died soon after birth. The few Dazap1Fn/Fn mice that survived could nonetheless live for more than a year. They appeared and behaved normally but were much smaller in size compared to their wild-type and heterozygous littermates. Both male and female Dazap1Fn/Fn mice were sterile. Males had small testes, and the seminiferous tubules were atrophic with increased numbers of apoptotic cells. The tubules contained many germ cells, including pachytene spermatocytes with visible XY-bodies and diplotene spermatocytes, but no post-meiotic cells. FACS analyses confirmed the absence of haploid germ cells, indicating spermatogenesis arrested right before the meiotic division. Female Dazap1Fn/Fn mice had small ovaries that contained normalappearing follicles, yet their pregnancy produced no progeny due to failure in embryonic development. The phenotypes of Dazap1 mutant mice indicate that DAZAP1 is not only essential for spermatogenesis, but also required for the normal growth and development of mice.

DAZAP1, an RNA-binding protein required for development and spermatogenesis, can regulate mRNA translation

“…While most Dazap1-deficient (and -hypomorphic) mice die perinatally due to growth defects, the few surviving Dazap1-hypomorphic male progeny contain no postpachytene spermatocytes, indicating roles for Dazap1 in normal growth, development, and spermatogenesis (Hsu et al 2008). Surviving Dazap1-hypomorphic female mice are also sterile (Hsu et al 2008).…”

“…While most Dazap1-deficient (and -hypomorphic) mice die perinatally due to growth defects, the few surviving Dazap1-hypomorphic male progeny contain no postpachytene spermatocytes, indicating roles for Dazap1 in normal growth, development, and spermatogenesis (Hsu et al 2008). Surviving Dazap1-hypomorphic female mice are also sterile (Hsu et al 2008). However, the molecular functions of Dazap1 and their relative contributions to these phenotypes remain unclear, although its ability to bind RNA (Tsui et al 2000a;Zhao et al 2001) suggests that Dazap1 is likely to have a role in regulating post-transcriptional gene expression.…”

Protein Acetylation and Spermatogenesis

“…Disruption of the Dazap1/ Prrp gene leads to developmental and reproductive defects in mice [40]. Expression of Dazap1/Prrp is predominantly observed in the testis [41,42], in which its gene products display a dynamic expression pattern with respect to the stage of spermatogenesis.…”

Transcription and post-transcriptional regulation of spermatogenesis

“…This hnRNP protein-DAZAP1-was isolated on the basis of its interaction with DAZ, a germ-cell-specific RNA-binding protein encoded on the Y chromosome that is deleted in 10 per cent of infertile men with idiopathic azoospermia (Reijo et al 1995(Reijo et al , 1996Tsui et al 2000). To determine the in vivo function of DAZAP1, Hsu et al (2008) generated Dazap1-mutant mice carrying either a floxed neomycin resistant (Fn) hypomorphic allele or a null allele. Both alleles caused widespread developmental defects, including perinatal lethality, retarded growth, obesity and male infertility.…”