Reduced fertility in mice deficient for the POU protein sperm-1

Abstract

Members of the POU-homeodomain gene family encode transcriptional regulatory molecules that play important roles in terminal differentiation of many organ systems. Sperm-1 (Sprm-1) is a POU domain factor that is exclusively expressed in the differentiating male germ cell. We show here that the Sprm-1 protein is expressed in the haploid spermatid and that 129͞Sv Sprm-1(؊͞؊) mice are subfertile when compared with wild-type or heterozygous littermates yet exhibit normal testicular morphology and produce normal numbers of mobile spermatozoa. Our data suggest that the Sprm-1 protein plays a discrete regulatory function in the haploid spermatid, which is required for the optimal function, but not the terminal differentiation, of the male germ cell.It is estimated that 15% of all married couples in the United States experience fertility problems, of which half of the cases are thought to result from infertility in the male (1). The diagnosis in 40-60% of cases of male infertility is idiopathic infertility, which, as the name implies, has an enigmatic etiology. Many of these males exhibit oligozoospermia, which is characterized by a reduction of sperm concentration in the ejaculate from greater than 50 million per ml to less than 10-20 million sperm per ml. But many still exhibit relatively normal concentrations of mobile spermatozoa.Spermatogenesis is a complex cellular differentiation process whereby a single diploid cell gives rise to thousands of highly specialized haploid spermatozoa (2, 3). The stem cells of the testis arise by invasion of the embryonic genital ridges by migrating primordial germ cells. These stem cells, known as type A spermatogonia, proliferate either to self-renew or to generate type B spermatogonia. Puberty is initiated by signals from the hypothalamic-pituitary axis, which direct the progression of type B spermatogonia to primary spermatocytes. The final cellular division in this process is the meiotic reduction of secondary spermatocytes that generates haploid spermatids. These spermatids exist as a syncytial bundle that undergoes dramatic morphological and genetic changes to produce functional, mobile spermatozoa in a process known as spermiogenesis. During this entire differentiation process germ cells maintain intimate contact with the supporting Sertoli cells, which, in response to hormonal stimuli from the pituitary and Leydig cells, provide the appropriate environment for germ cell maturation.It was thought previously that a surge of RNA synthesis immediately before the meiotic reduction, along with RNA storage and translational regulation, provided sufficient resources during spermiogenesis to obviate the need for de novo haploid gene transcription (4). However, advances in cloning strategies have led to the identification of many genes that are not transcribed until after the meiotic reduction (5). Indeed, it has been shown recently that many haploid-expressed genes are regulated by the cyclic AMP-responsive element modulator protein CREM (6, 7).Results of the analyses of mic...

Heat-shock protein HSPA4 is required for progression of spermatogenesis

“…Background-related differences in male infertility phenotype have been reported in other mutations (Pearse et al 1997, Yu et al 2000, Adham et al 2001. We have observed increased incidence of male infertility among Hspa4-null mice in F2 generation, which contain a high level of inter-individual genetic variability.…”

Male Germ Cell Gene Expression

“…The only effect of a targeted mutation in the Erg4 gene was disruption of male germ cell development during the meiotic phase (Tourtellotte et al, 1999). Also, a knockout of the gene for SPRM-1, a POU-homeodomain gene expressed only in male germ cells during the postmeiotic phase, produced subnormal fertility (Pearse et al, 1997). In addition, a germ cell-specific subunit of the general transcription factor TFIIA was found to be upregulated in pachytene spermatocytes, along with several RNA polymerase II and III factors (Han et al, 2001).…”

CIB1 Is Essential for Mouse Spermatogenesis

“…The possible regulatory roles of CIB1 in spermatogenesis were tested first by determining which gene expression patterns were altered in the Cib1 Ϫ/Ϫ testis via RT-PCR. We initially examined the expression of stage-specific marker genes that appear during meiosis, i.e., Hsp70-2 (heat shock protein, chaperone) and Sprm-1 (POU homeodomain domain [5,15,25,36]) but found comparable mRNA expression levels in Cib1 ϩ/ϩ and Cib1 Ϫ/Ϫ testis samples (Fig. 4A).…”