Table 1.

In vivo models with Flcn inactivation

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