Table 1.
Summary of phenotypes observed in NMD factor loss-of-function animal models.
| NMD factor | Functions | Species | Genotype | Phenotype | References |
|---|---|---|---|---|---|
| UPF1/SMG2 | ATP-dependent 5′−3′ RNA helicase; recruits UPF2 and UPF3 near the PTC; phosphorylated by SMG1 and activates NMD | C. elegans | Loss-of-function mutants | Viable, mild defects in tail, bursal, and vulval development | Hodgkin et al. (1989) |
| Drosophila | Missense and nonsense mutations | Lethality during larval development, rescued by loss of Gadd45 | Metzstein and Krasnow (2006); Avery et al. (2011); Nelson et al. (2016) | ||
| Zebrafish | Knockdown by morpholinos | Embryonic lethality, brain patterning and midbrain–hindbrain boundary defects, brain necrosis, somitogenesis impairment | Wittkopp et al. (2009) | ||
| Mouse | Global knockout | Embryonic lethality, apoptosis at blastocyst stage | Medghalchi et al. (2001) | ||
| UPF2/SMG3 | Branch-specific NMD factor; recruited to the EJC via UPF3B interactions; bridges UPF1 and the EJC | C. elegans | Loss-of-function mutants | Viable, mild defects in tail, bursal, and vulval development | Hodgkin et al. (1989) |
| Drosophila | Null mutant | Lethality during larval development, defects in NMJ synaptic transmission | Metzstein and Krasnow (2006); Long et al. (2010); Avery et al. (2011) | ||
| Drosophila | Brain-specific knockdown by RNAi | Impaired long-term memory | Johnson et al. (2019) | ||
| Zebrafish | Knockdown by morpholinos | Embryonic lethality, developmental defects similar to Upf1 knockdown | Wittkopp et al. (2009) | ||
| Mouse | Global knockout | Embryonic lethality between E3.5 and E7.5 | Weischenfeldt et al. (2008) | ||
| Mouse | Liver-specific knockout | Perinatal lethality, impaired liver development, activated DNA damage response | Thoren et al. (2010) | ||
| Mouse | Forebrain-specific knockout | Impaired hippocampal synaptic plasticity and long-term memory, deficits in social behaviors and behavioral inflexibility, neuroinflammation | Johnson et al. (2019) | ||
| UPF3/SMG4 | Branch-specific NMD factor; interacts with the EJC; recruits UPF2; in vertebrates, UPF3A is a partially redundant but less active paralog of UPF3B | C. elegans | Loss-of-function mutants | Viable, mild defects in tail, bursal, and vulval development | Hodgkin et al. (1989) |
| Drosophila | Null mutant | Viable, fertile, no severe developmental defects | Avery et al. (2011) | ||
| Zebrafish | Knockdown by morpholinos | Upf3a: weak brain patterning defect, viable; Upf3b: no apparent phenotype; double knockdown: mild phenotype similar to Upf1 mutant, few with brain necrosis, 19% lethality at 5 days post-fertilization | Wittkopp et al. (2009) | ||
| Mouse | Upf3a knockout | Global knockout: embryonic lethality between E4.5 and E8.5; male germ cell-specific knockout: spermatogenesis defects; olfactory epithelium-specific knockout: reduced NMD target abundance | Shum et al. (2016) | ||
| Mouse | Upf3b knockout | Impaired fear-conditioned learning and prepulse inhibition, dendritic spine maturation deficits | Huang et al. (2018) | ||
| SMG1 | PI3K-related kinase; phosphorylates UPF1 at S/TQ motifs and activates NMD | C. elegans | Loss-of-function mutants | Viable, mild defects in tail, bursal, and vulval development | Hodgkin et al. (1989) |
| Drosophila | Null mutant | Viable, fertile, impaired synaptic transmission, impaired synaptic vesicle recycling | Metzstein and Krasnow (2006); Long et al. (2010) | ||
| Zebrafish | Knockdown by morpholinos | No phenotype observed in embryos | Wittkopp et al. (2009) | ||
| Mouse | Global knockout | Embryonic lethality, developmental arrest at E8.5 | McIlwain et al. (2010) | ||
| SMG5 | NMD effector; recruited near the PTC by phosphorylated UPF1; promotes deadenylation and RNA decay; promotes dephosphorylation of UPF1 by recruiting PP2A | C. elegans | Loss-of-function mutants | Viable, mild defects in tail, bursal, and vulval development | Hodgkin et al. (1989) |
| Drosophila | Loss-of-function mutants | Developmental delay in larval stage and lethality during pupariation, synthetic lethality between Smg5 hypomorph and Smg1 null | Nelson et al. (2018) | ||
| Zebrafish | Knockdown by morpholinos | Embryonic lethality, developmental defects similar to Upf1 knockdown | Wittkopp et al. (2009) | ||
| SMG6 | Endonuclease; recruited by phosphorylated UPF1; cleaves mRNAs near the PTC | C. elegans | Loss-of-function mutants | Viable, mild defects in tail, bursal, and vulval development | Hodgkin et al. (1989) |
| Drosophila | Loss-of-function mutants | Partially functional NMD, moderate reduction in viability, growth disadvantage of mutant cells when competing with wild-type cells, impaired NMJ synaptic transmission | Long et al. (2010); Frizzell et al. (2012) | ||
| Zebrafish | Knockdown by morpholinos | Embryonic lethality, developmental defects similar to Upf1 knockdown | Wittkopp et al. (2009) | ||
| Mouse | Global knockout | Embryonic lethality at the blastocyst stage | Li et al. (2015) | ||
| SMG7 | NMD effector; promotes deadenylation and RNA decay; promotes dephosphorylation of UPF1 | C. elegans | Loss-of-function mutants | Viable, temperature-sensitive defect in NMD | Cali et al. (1999) |
| Zebrafish | Knockdown by morpholinos | Elongated hindbrain, altered midbrain to hindbrain boundary, stacked somites, bent tails | Wittkopp et al. (2009) |