Table 1.
Organism | Type of model | Target tissue | Phenotype | Pathways affected | Reference |
---|---|---|---|---|---|
Mouse | GEM, Cre-lox | Kidney, distal nephron | Large cystic kidneys, renal failure | ↑AKT-mTOR activation ↑Raf/MEK/Erk1/2 axis |
(Baba et al., 2008) |
Mouse | GEM, Cre-lox | Kidney, distal nephron | Large cystic kidneys, cystic RCC, renal failure | ↑mTOR activation | (Chen et al., 2008) |
Mouse | GEM, Cre-lox | Heterozygous deletion in whole animal | Late onset kidney tumors w/ LOH | ↑AKT, mTORC1 & mTORC2 activation | (Hasumi et al., 2009) |
Mouse | GEM, gene trap KO plus ENU treatment | Heterozygous deletion in whole animal | Cysts and low frequency of oncocytic tumors | ↓mTORC1 activation | (Hartman et al., 2009) |
Mouse | GEM, gene trap KO | Heterozygous deletion in whole animal | Cysts, adenomas & multicystic kidneys | Both ↑ & ↓ mTORC1 activation; ↑ERK1/2 | (Hudon et al., 2010) |
Mouse | GEM, Cre-lox | Skeletal muscle | Red colored muscle & ↑mitochondrial number in muscle | ↑PGC1α expression & mitochondrial biogenesis | (Hasumi et al., 2012) |
Mouse | GEM, Cre-lox | Epidermal layer of skin | Delayed eye opening, wavy fur, hair loss, epidermal hyperplasia | ↑mTORC1 activation | (Medvetz et al., 2012) |
Mouse | GEM, Cre-lox | Heart | Cardiac hypertrophy & cardiac dysfunction | ↓pAMPK, ↑mTOR, ↑PGC1α expression & mitochondrial biogenesis | (Hasumi et al., 2014) |
Mouse | GEM, Cre-lox | Lung, alveolar epithelial type II cell | Alveolar enlargement, impaired lung function | ↓E-cadherin-LKB1-AMPK axis | (Goncharova et al., 2014) |
Mouse | GEM, Cre-lox | Kidney, proximal tubule | Kidney cysts & tumors | ↑AKT-mTOR activation ↑TGF-β pathway activation |
(Chen et al., 2015) |
Mouse | GEM, Cre-lox | Adipose tissue | ↑beige adipocytes in WAT; high energy expenditure; resist cold exposure | ↑pAMPK-PGC1α-ERRα axis & mitochondrial biogenesis | (Yan et al., 2016) |
Mouse | GEM, Cre-lox | Adipose tissue | ↑beige adipocytes in WAT; resist cold exposure | ↑TFE3 activity & targets PGC1α, PGC1β,GPNMB; ↑mitochondrial biogenesis |
(Wada et al., 2016) |
Mouse | GEM, transgenic | Flcn H255Y transgene in kidney-targeted Flcn KO background | Cannot rescue kidney-targeted Flcn KO phenotype | Acts as Flcn KO allele; strong mutation | (Hasumi et al., 2017) |
Mouse | GEM, transgenic | Flcn K508R transgene in kidney-targeted Flcn KO background | Partially, not entirely rescues kidney-targeted Flcn KO phenotype | Acts to partially reverse Flcn KO phenotype; weak mutation & potential DN function | (Hasumi et al., 2017) |
Yeast (S. pombe) | Replacement of bhd ORF with kanamycin cassette | Deletion in whole organism | None evident | ↑amino acid permeases & amino acids suggesting ↓Tor2 activity | (van Slegtenhorst et al., 2007) |
Fruit fly (D. melanogaster) | DBHD dsRNA-mediated RNAi | Knockdown in whole organism | Defects in male germline stem cell maintenance in testis | DBHD functions in parallel or downstream of JAK-STAT & Dpp pathways | (Singh et al., 2006) |
Fruit fly (D. melanogaster) | DBHD null allele | Homozygous knockout in whole organism | Growth retardation, small body, larval lethality | ↑autophagy; rescue by leucine feeding suggesting dTOR inhibition in DBHD−/− | (Liu et al., 2013) |
Round worm (C. elegans) | flcn-1 (ok975) null allele | Knockout in whole organism | Increased resistance to oxidative stress | ↑AAK-2, ↑autophagy, ↑ATP levels, ↓apoptosis | (Possik et al., 2014) |
Zebrafish (D. rerio) | flcn knockout allele using morpholino anti-sense oligonucleotide | Knockout in whole organism | 18 somite stage developmental arrest; hydrocephalus ; tail circulatory defects | Disruption of the cell cycle and loss of proliferation in embryonic brain | (Kenyon et al., 2016) |
Abbreviations: GEM, genetically engineered model; RCC, renal cell carcinoma; Cre, cre recombinase; lox, flanked by loxP sites; LOH, loss of heterozygosity; KO, knockout; ORF, open reading frame; WAT, white adipose tissue; DN, dominant negative; AAK-2, AMPK ortholog