Disease relevance of Dazl

• DAZ is an RNA-binding protein encoded by a region on the Y chromosome implicated in infertility, and DAZ-like (Dazl) proteins are master regulators of germ line gene expression in all animals [1].
• The DAZLA gene may be involved in some familial cases of autosomal recessive male infertility [2].

High impact information on Dazl

• Disruption of the Dazla gene leads to loss of germ cells and complete absence of gamete production, demonstrating that Dazla is essential for the differentiation of germ cells [3].
• It has also been shown that a Dazla homologue is essential for spermatogenesis in Drosophila [3].
• We have focussed on mouse vasa homologue (Mvh), a gene that is essential for male gametogenesis, and show that Dazl stimulates translation via the Mvh 3'-UTR [4].
• This gene, Dazla (Daz like, autosomal), is autosomal, located on chromosome 17 and apparently single copy [5].
• Here, we show that the postmigratory germ cell-specific genes Mvh, Dazl and Scp3 are demethylated in germ cells, but not in somatic cells [6].

Biological context of Dazl

• Using an inbred C57BL/6 background, we show that Dazl is required for embryonic development and survival of XY germ cells [7].
• It was concluded that in the absence of Dazl, germ cells can complete mitosis, and embark on functional differentiation but that, in both sexes, progression through meiotic prophase requires this RNA binding protein [8].
• Dazl encodes an RNA-binding protein essential for spermatogenesis [9].
• As a result, most seminiferous tubules of Dazl -/- mice only contain actively proliferating A(s), A(pr), and A(al) spermatogonia, with cell production being equaled by apoptosis of these cells [9].
• We used cDNA microarrays firstly to investigate normal gene expression in the wild-type (wt) testis and secondly to gain a better insight into the effect of the disruption of the Dazl gene on spermatogenesis [10].

Anatomical context of Dazl

• Dazl deficiency leads to embryonic arrest of germ cell development in XY C57BL/6 mice [7].
• By E15.5, most remaining germ cells in XY Dazl-/- embryos exhibited apoptotic morphology, and XY Dazl-/- gonads contained increased numbers of TUNEL-positive cells [7].
• Functional differentiation of spermatogonia associated with detection of c-kit positive cells did not depend upon expression of Dazl [8].
• Furthermore, in the +/- mice, the enhanced plasma inhibin B implies a role for Dazl protein within the oocyte either from more small follicles or increased inhibin B production from each follicle [11].
• To gain more insight regarding the timing of the spermatogenic arrest in Dazl -/- mice, we studied the spermatogonial cell types present in testis sections and in seminiferous tubular whole mounts [9].

Other interactions of Dazl

• Moreover, the cells expressed detectable levels of protein markers specific for germ cells such as Dazl, and specific for germ line stem cells such as Oct-4, a transcription factor, and GFRalpha-1, the receptor for glial cell line-derived neurotrophic factor (GDNF) [12].
• In a directed tri-hybrid assay the strongest interaction was with the consensus (GUn)n. This motif is found in the 5' UTR of CDC25C whose homologue is thought to be the target of Boule, the Dazl homologue in flies [1].
• Taken together these data support Sycp3 as a biologically relevant target of Dazl-mediated translation in mammals [13].

Analytical, diagnostic and therapeutic context of Dazl

• Lentiviral-mediated transgenesis was used to produce rats expressing a short hairpin RNA targeting Dazl, a gene expressed in germ cells and required for fertility in mice [14].
• Using a combination of immunoprecipitation and microarray analysis, we have identified a number of mRNAs that are bound by the murine Dazl protein both in vivo and in vitro [4].
• Spermatogenesis in testes of Dazl null mice after transplantation of wild-type germ cells [15].
• Southern blot analysis showed that DAZLA is autosomal in all mammals tested and that DAZ has been recently translocated to the Y chromosome, sometime after the divergence of Old World and New World primates [16].
• In situ hybridization shows that Dazla expression in mouse testis is restricted to premeiotic stages IV-VI of spermatogenesis [17].

References