Table 1. Mouse Models of Autophagy Impairment with Clear Developmental Phenotypes.
| Molecule and Role in Autophagy | Mouse Model Allele Symbol and Type | Type of Mutation | Key Aspects of the Phenotype | Reference | |
|---|---|---|---|---|---|
| Ambra1: WD40 protein promotes Vps34 complex formation (autophagosome nucleation) | ambra1gt/gt (all tissues) | gene trap allele: Ambra1Gt(pGT1.8geo)1Fcec | gene trap insertion predicted to cause a 459 aa C-terminal truncation; fusion transcript, but no protein, detected | decreased autophagy, increased apoptosis and cell proliferation in embryonic brain; neural tube defects and embryonic lethality | Fimia et al., 2007 |
| Atg5: ubiquitin-like protein covalently modifies Atg12 and binds Atg16L to promote LC3-PE recruitment to autophagosome membranes (autophagosome elongation) | atg5-/- (all tissues) | knockout allele: Atg5tm1Nmz | neomycin-resistance (neo) gene replaces the transcription start site and first two exons | perinatal death due to nutrient and energy depletion; suckling defect; increased apoptosis in embryos | Kuma et al., 2004; Qu et al., 2007 |
| atg5-/flox (tissue-specific) | conditional allele: Atg5tm1Myok (floxed) | loxP sites flank exon 3 and neo cassette; Cre removes both exon 3 and neo | |||
| Atg5tm1Myok combined w/Tg(Nes-cre)1Kln transgenic (Cre driver) | Cre expressed in neuronal and glial precursors by e11.0 (Nestin promoter) | ubiquitin-positive inclusions in the brains of e15.5 embryos and postnatal mice, early onset neurodegeneration | Hara et al., 2006 | ||
| Atg5tm1Myok combined w/Tg(Zp3-cre)93Knw transgenic (Cre driver) | Cre expressed in female germline (Zp3 promoter) | null embryos derived from Atg5-deficient eggs fail to develop beyond the eight-cell stage; Atg5-deficient eggs fertilized by wild-type sperm are normal | Tsukamoto et al., 2008 | ||
| Atg5tm1Myok combined w/Cd19tm1(cre)Cgn transgenic (Cre driver) | Cre expressed throughout B lymphocyte development (Cd19 promoter) | the pro-B to pre-B cell transition is defective | Miller et al., 2008 | ||
| Atg7: E1 ligase-like protein activates LC3-I and Atg12 (autophagosome elongation) | atg7-/- (all tissues) | conditional allele: Atg7tm1.1Tchi | loxP sites flank exon 14 | excised during oogenesis, this allele results in a similar phenotype to Atg5tm1Myok/Tg(Zp3-cre)93Knw as above | Komatsu et al., 2005 |
| atg7-/flox (tissue-specific) | combined w/Tg(Nes-cre)1Wme transgenic (Cre/Flp) | this Nestin-Cre, in which Cre has a nuclear localization signal, drives variable/mosaic activity by e10.5, detectable in all adult tissues examined, including the germline | progressive deficits in motor function and death a few months after birth | Komatsu et al., 2006 | |
| combined w/Tg(Pcp2-cre)2Mpin transgenic (Cre/Flp) | Cre expressed in Purkinje cells starting at P6 and complete 2-3 weeks postpartum (L7/Pcp2 promoter) | degeneration of the axon terminals during postnatal brain development | Komatsu et al., 2007 | ||
| Beclin 1/Atg6: subunit of the Vps34 complex (autophagosome nucleation) | becn1-/- (all tissues) | knockout allele: Becn1tm1Blev | neo replaces exons 1 and 2 | abnormal ectodermal layer with reduced cavitation and early embryonic lethality | Qu et al., 2003; Qu et al., 2007 |
| knockout allele: Becn1tm1Htz | neo replaces exons 1 and 2 and 1.6 kb of upstream sequence | widespread cell death, reduced embryo size | Yue et al., 2003. |
Allele symbols are standard according to http://www.informatics.jax.org.