Role of Dicer In Vivo

Knockout experiments indicated that Dicer is essential for vertebrate development. Disruption of the Dicer gene in mice arrests embryogenesis at day 8.5 (Bernstein et al. 2003), while mice with a strong hypomorphic mutation, resulting from the deletion of the first two Dicer exons, die between 12.5 and 14.5 days of gestation and display defects in angiogenesis (Yang et al. 2005). Effects of different tissue-specific Dicer knockouts have also been analyzed. Mouse oocytes lacking Dicer fail to accumulate mature miRNAs and are unable to progress through first meiotic division, displaying disorganized spindles and chromosome congression defects (Murchison et al. 2007; Tang et al. 2007). These observations suggest that miRNAs play an essential role during the earliest stages of embryonic development, when maternally encoded transcripts have to undergo specific downregulation (Giraldez et al. 2006). In addition, Dicer may be involved in the protection of germ cells from the movement of transposable elements, since in oocytes lacking Dicer transcripts levels of some transposons are elevated (Murchison et al. 2007). In mice with the epidermal-specific Dicer knockout, proper morphogenesis and maintenance of hair follicles is affected (Andl et al. 2006). Dicer function was also found to be essential for lung epithelium morphogenesis (Harris et al. 2006) and limb development (Harfe et al. 2005).

Dicer-deficient mouse embryonic stem (ES) cells display proliferation and differentiation defects and, as expected, are defective in dsRNA-induced RNAi and generation of miRNAs (Kanellopoulou et al. 2005; Murchison et al. 2005). Epigenetic silencing of centromeric repeats is also reduced in these cells (Kanellopoulou et al. 2005). Likewise, in the chicken-human hybrid DT40 cell line, loss of Dicer leads to premature sister chromatid separation due to abnormalities in heterochromatin formation (Fukagawa et al. 2004). Dicer function was also found to be essential for zebrafish development and many processes in C. elegans. In Drosophila , Dicer-1, which is involved in miRNA biogenesis, is likewise an essential gene (reviewed by Wienholds and Plasterk 2005; Giraldez et al. 2006). Most of the phenotypes associated with Dicer knockouts are probably mainly caused by the depletion of miRNAs. However, other mechanisms controlled by Dicer, related to RNAi, such as the formation of heterochromatic structures and centromeric silencing, may also contribute to developmental or cellular defects discussed above (reviewed by Grewal and Jia 2007; Zaratiegui et al. 2007).

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