The importance of NMD is exemplified by the findings that mouse embryos that cannot perform NMD because they lack a key NMD protein, Upf1, resorb shortly after implantation (Medghalchi et al., 2001). Furthermore, blastocysts that have the same defect, isolated 3.5 days post-coitum, undergo apoptosis in culture after a brief growth period (Medghalchi et al., 2001). The inviability of NMD-deficient embryos and cells probably reflects the combined failure to regulate natural substrates properly and eliminate transcripts that were generated in error. Note that, Upf1 has been shown to function in other pathways, as well as NMD (see below), which may also contribute to the observed inviability.

NMD in mammalian cells is a consequence of a pioneer round of translation (Chiu et al., 2004; Ishigaki et al., 2001; Lejeune et al., 2004). As illustrated in the poster, precursor (pre)-mRNA in the nucleus is bound to by the major nuclear cap-binding protein (CBP) CBP80-CBP20 heterodimer and, after 3′-end formation, the major nuclear poly (A)-binding protein (PABP) PABPN1 (Chiu et al., 2004; Ishigaki et al., 2001). PremRNA splicing generates spliced mRNA that is bound by CBP80, CBP20, PABPN1 and the major cytoplasmic PABPC (Chiu et al., 2004; Ishigaki et al., 2001; Lejeune et al., 2004) as well as an exon junction complex (EJC) of proteins that is deposited, as a consequence of splicing,~ 20-24 nucleotides upstream of each exon-exon junction (Le Hir et al., 2000a; Le Hir et al., 2000b). Constituents of EJCs include Y14, RNPS1, SRm160, REF/Aly, UAP56, Magoh, Pnn/DRS, eIF4AIII, PYM and Barentsz/MLN51 (Bono et al., 2004; Chan et al., 2004; Custodio et al., 2004; Degot et al., 2004; Ferraiuolo et al., 2004; Kataoka et al., 2000; Kim et al., 2001; Le Hir et al., 2001; Le Hir et al., 2000a; Le Hir et al., 2000b; Lejeune et al., 2002; Li et al., 2003; Luo et al., 2001; Palacios et al., 2004; Shibuya et al., 2004). The EJC also contains additional proteins, including the NMD factors Upf3 (also called Upf3a) or Upf3X (also called Upf3b), Upf2 and, presumably transiently, Upf1 (Kim et al.,