Table 3.

Transgenic mouse models for bile duct defects, cholestasis and cholangiopathies.

Disease	Gene	Phenotype	Ref
Alagille syndrome	Jag1dDSL/+	Jag1dDSL/+ pups were recovered at lower than expected frequencies (35% rather than 50%). No jaundice at any stage. Large decrease in Sox9+ ductal plate cells (>95%) at E18, a 75% reduction in bile ducts at P3-P7, and ductular reaction at P30, which is partially rescued in Jag1dDSL/+Rumi+/− (Poglut1) mice.	[50]
	Jag1dDSL/+Rumi+/−(back-crossed to C57BL/6 J background for >10 generations)
	Jag1dDSL/+Lfng+/−	No phenotype at birth, though all double heterozygous mice and Jag1dDSL/+ alone were recoved at lower than expected frequencies. Massive bile duct proliferation in adult Jag1dDSL/+Lfng+/− and Jag1dDSLRfng+/− mice.	[95]
		Small but significant increase in number of bile ducts in adult Jag1+/−Mfng+/−mice.
	Jag1dDSL/+Rfng+/−
	Jag1dDSL/+Mfng+/− (back-crossed to C57BL/6 J background)
	Jag1dDSL/+Notch2del1/+ (mixed C57BL/6 J × 129S1/SvImJ background)	Half of Jag1dDSL/+Notch2del1/+mice die the first week after birth. Jaundice at P3. Absence of bile ducts.	[96]
	Jag1Ndr/Ndr (mixed C3H x C57bl6 background)	Ca 10% of Jag1Ndr/Ndrmice survive to postnatal day 10. Pups show delayed bile duct development, bile duct dysmorphology and cholestasis. 5% survive to adulthood, these show rescue of cholestasis with persistent bile duct dysmorphology. On a pure C3H background, Jag1Ndr/Ndr mice are embryonic lethal.	([51]; [47])
	Jag1loxP/dDSL; Alfp-Cre	Partially penetrant (50%) bile duct proliferation in conditional/null Jag1 mice.	[97]
	Jag1lox/lox;SM22-Cre	Jag1 is required in portal vein mesenchyme (Sm22-expressing) rather than endothelial cells or hepatoblasts. Absence of Jag1 from portal vein mesenchyme results in a failure to from bile ducts and postnatal jaundice.	([5]; [97])
	Notch2del1/del1 (mixed C57BL/6 J × 129S1/SvImJ background)	No bile ducts at p0. Later analyses precluded by kidney-related postnatal lethality.	[96]
	Notch2loxp/del2Alb1-Cre	Jaundice at P3, focal necrosis in liver. Scattered cholangiocytes but no bile ducts at P7.	[48]
	Notch2loxp/del3Alb1-Cre
	Notch2lox/lox;AlbCre	Defective ductal plate remodeling, biliary cells present, but absence of bile ducts. Portal inflammation, fibrosis, bile duct dilation, and proliferation.	[98]
	RbpjloxP/Δ;Foxa3-Cre or	Fewer ductal plate cells at E16.5 and P0, and fewer bile ducts at P0 in RbpjloxP/Δ;Foxa3-Cre mice. When RBPj is deleted later, using AFP-Cre, there is a less severe reduction in peri-portal ductal cells, but similarly reduced number of bile ducts at postnatal stages.	[99]
	RbpjloxP/loxP;AFP-Cre
	Rbpjloxp/loxpHnf6loxp/loxpR26ZG+/+Alb1-Cre	Bile ducts absent at postnatal stages, adult conversion of hepatocytes to cholangioytes driven by Tgfβ rescues the biliary tree.	[54]
	Sox9loxp/loxp;Alfp-cre	Delayed ductal plate remodeling. Normal bile ducts by the age of 5 weeks.	[100]
Arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome	Alfp-Cre; Vps33bloxp/loxp	Cholestasis and fibrosis.	[101]
ARPKD	Pkhd1ex40 (Fibrocystin/polyductin)	Bile duct cysts	[102]
Autosomal recessive polycystic kidney disease & Caroli syndrome
	Pkhd1del4/del4
			[45]
		Bile duct proliferation, progressive bile duct enlargement and portal fibrosis.
		Bilirubin clearance normal.
PLD-ADPKD: Polycystic liver disease associated with autosomal dominant polycystic kidney disease	Pkd1+/−	Late onset liver cysts (27% with liver cysts at 9–14 months, 87% in older mice)	[103]
	Pkd1+/del17–21βgeo
	pCx-Cre;Pkd1loxp/−or
	pCx-Cre;Pkd2loxp/−
			[104]
	TPK1 and TPK3 mice (transgenic mice expressing ¨30 extra copies of human PKD1, as well as TSC2)
		Liver cysts in aged heterozygous mice (>19 months). Homozygous mice are embryonic lethal.
			[105]
	Pkd2WS26/wS25
		Liver cysts by 4 weeks of age.
			[107]
			[108]
		Inflammation, bile duct proliferation, and liver cysts.
	Hypomorphic mice
		¨20% of Pkd2WS26/wS25 mice display liver cysts between 4 and 10 weeks of age.
Biliary atresia	Sox17−/− SRY-related HMG-box 17	Smaller liver, inflammation, extraheptic bile duct stenosis and atresia.	[109]
		Sox17 is required in gallbladder rather than hepatoblasts
Autosomal dominant polycystic liver disease	pCx-Cre;Prkcshloxp/loxp	Liver cysts.	[110]
	pCx-Cre;Sec63loxp/loxp
Primary biliary cholangitis	Dominant negative TGF-βRII (driven by CD4 promoter lacking the CD8 silencer)	Liver fibrosis and bile duct destruction.	[111]
		Onset is delayed by IL-12p35 deletion.	[113]
		IL-12p40 deletion protects against liver inflammation in Dn TGF-βRII mice.	[114]
	Dn TGF-βRII IL-12p35 −/−
	Dn TGF-βRII IL-12p40 −/−
Primary biliary cholangitis	IL-2Rα−/−	Portal inflammation and biliary ductular damage.	[115]
	IL-2Rα−/−IL12-p40−/−
Primary biliary cholangitis/ Sjögrens syndrome
		Compared to IL-2Rα −/− mice alone, worsened portal inflammation and bile duct damage, but reduced colitis in IL-2Rα−/−IL12-p40−/−mice.	[116]
	NOD.c3c4 mice	Autoimmune polycystic destructive cholangitis, granuloma formation, and eosinophilic infiltration in addition to extrahepatic bile duct effects.	([117]; [118])
	Ae2a,b−/−	Partially penetrant portal inflammation and bile ducts destruction (4/11 mice with severe or moderate inflammation).	[119]
	Cl(−)/HCO(3)(−) anion exchanger 2 (AE2)
	Scurfy mice (Foxp3sf mutant)	Portal inflammation and bile duct destruction.	[120]
	Faslpr/lpr	Portal inflammation and cholangitis of small intrahepatic bile ducts.	[121]
	MRL (genetic background)/lpr (lymphoproliferation) mice
Primary sclerosing cholangitis	Mdr2−/−	Sex-dependent liver disease. Inflammation and ductular reaction in large portal tracts. Fibrosis and bile duct destruction.	([122]; [123]; [124])
	(Abcb4 or ATP-binding cassette, sub-family B (MDR/TAP), member 4)
	CDH1loxp/loxp; Alb-Cre (CDH1ΔL, Liver-specific E-cadherin knockout)	Periportal inflammation and periductal fibrosis leading to liver tumors.	[125]
	Krt19-Cre; CDH1loxp/loxp	E-cad is required primarily in bile ducts rather than hepatocytes to avoid cholestasis.
	Adenovirus-Cre; CDH1loxp/loxp
Progressive Familial Intrahepatic Cholestasis (PFIC2)	Abcb11 (ATP-binding cassette, sub-family B (MDR/TAP), member 11, aka sister of P-glycoprotein (Spgp) or bile salt export pump (BSEP))	Altered hepatocyte canalicular morphology and bile salt secretion defects, but mild/no cholestasis overall.	[126]
			[127]
		Cholic acid diet in these mice induces severe cholestasis, bile duct proliferation and cholangitis.
PFIC-like inherited cholestasis	Atp11c	Cholestasis which is worsened on a cholic acid diet.	[128]
	ATPase Phospholipid Transporting 11C
		Hyperbilirubinemia at postnatal stages that resolves with age.
Cystic fibrosis liver disease	Cftr−/−	Hepatosteatosis, focal cholangitis, and bile duct proliferation. Focal biliary cholangitis in aged (1 year) mice.	[130]
	Cystic fibrosis transmembrane conductance regulator
			[131]
		Oral dextran induction of colitis induced greater bile duct injury with inflammation and bile duct proliferation.
Erythropoietic protoporphyria	fch/fch (ferrochelatase mutation)	Bile duct proliferation and biliary fibrosis.	[132]
General liver inflammation and liver fibrosis	Fra-1 overexpression driven byhistocompatibility complex class I antigen H2-Kb(H2) promoter (Fra-1tg) mice & Fra-1tgrag2−/−	Portal inflammation, ductular proliferation and biliary fibrosis. Fibrosis was attenuated but not completely rescued by Rag2 deletion.	[133]
Canaliculi and bile duct development defects	Lkb1loxp/loxp; Alb-Cre	Altered hepatocyte canalicular morphology and poorly formed/absent bile ducts	[134]
	Ctnnb1loxp/loxp; Foxa3-Cre	Decrease in overall liver size and bile duct paucity	[135]
Role of bile duct innervation	M3-R−/− (muscarinic 3 receptor)	Decreased bile flow but no liver injury or cholestasis. However, 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) feeding induced more severe liver injury with obstruction of bile ducts by porphyrin plugs.	[136]
Zellweger spectrum disorder (includes liver fibrosis)	Pex1G844D (peroxisomal biogenesis factor 1)	Bile deposits and bile duct proliferation (?)	[137]