title: Loss of cilia causes embryonic lung hypoplasia, liver fibrosis, and cholestasis in the talpid3 ciliopathy mutant.
abstract: Sonic hedgehog plays an essential role in maintaining hepatoblasts in a proliferative non-differentiating state during embryogenesis. Transduction of the Hedgehog signaling pathway is dependent on the presence of functional primary cilia and hepatoblasts, therefore, must require primary cilia for normal function. In congenital syndromes in which cilia are absent or non-functional (ciliopathies) hepatorenal fibrocystic disease is common and primarily characterized by ductal plate malformations which underlie the formation of liver cysts, as well as less commonly, by hepatic fibrosis, although a role for abnormal Hedgehog signal transduction has not been implicated in these phenotypes. We have examined liver, lung and rib development in the talpid(3) chicken mutant, a ciliopathy model in which abnormal Hedgehog signaling is well characterized. We find that the talpid(3) phenotype closely models that of human short-rib polydactyly syndromes which are caused by the loss of cilia, and exhibit hypoplastic lungs and liver failure. Through an analysis of liver and lung development in the talpid(3) chicken, we propose that cilia in the liver are essential for the transduction of Hedgehog signaling during hepatic development. The talpid(3) chicken represents a useful resource in furthering our understanding of the pathology of ciliopathies beyond the treatment of thoracic insufficiency as well as generating insights into the role Hedgehog signaling in hepatic development.
authors.affiliation: Division of Developmental Biology; The Roslin Institute and R(D)SVS; University of Edinburgh; Midlothian, UK.
authors.forename: Megan G
authors.initials: MG
authors.lastname: Davey
authors.affiliation: Division of Developmental Biology; The Roslin Institute and R(D)SVS; University of Edinburgh; Midlothian, UK.
authors.forename: Lynn
authors.initials: L
authors.lastname: McTeir
authors.affiliation: Division of Developmental Biology; The Roslin Institute and R(D)SVS; University of Edinburgh; Midlothian, UK.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Barrie
authors.affiliation: Division of Developmental Biology; The Roslin Institute and R(D)SVS; University of Edinburgh; Midlothian, UK.
authors.forename: Lucy J
authors.initials: LJ
authors.lastname: Freem
authors.affiliation: Division of Developmental Biology; The Roslin Institute and R(D)SVS; University of Edinburgh; Midlothian, UK.
authors.forename: Louise A
authors.initials: LA
authors.lastname: Stephen
mesh_terms: D000818:Animals; D001659:Biliary Tract / Q000002:abnormalities / Q000196:embryology; D018797:Cell Cycle Proteins / Q000235:genetics*; D002642:Chick Embryo; D002645:Chickens; D002779:Cholestasis / Q000196:embryology* / Q000473:pathology; D002923:Cilia / Q000473:pathology*; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism; D008103:Liver Cirrhosis / Q000150:complications / Q000196:embryology* / Q000473:pathology; D008168:Lung / Q000002:abnormalities* / Q000196:embryology* / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D000072079:Patched Receptors; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D053823:Hedgehog Proteins; D000072079:Patched Receptors; D011956:Receptors, Cell Surface
keywords: GLI; KIAA0586; SHH; TALPID3; cholestasis; cilia; ciliopathy; liver; pulmonary hypoplasia; short-rib polydactyly
references.citation: Curr Opin Gastroenterol. 2011 May;27(3):268-75
references.pmid: 21423008
references.citation: Dev Biol. 2000 Nov 1;227(1):12-27
references.pmid: 11076673
references.citation: J Pediatr Surg. 2007 Sep;42(9):1555-60
references.pmid: 17848248
references.citation: PLoS One. 2011;6(9):e23943
references.pmid: 21912653
references.citation: Dev Dyn. 2013 Aug;242(8):923-31
references.pmid: 23613203
references.citation: Arch Dis Child. 1977 Oct;52(10):758-65
references.pmid: 931421
references.citation: J Anat. 2003 Nov;203(5):505-12
references.pmid: 14635803
references.citation: Gastroenterology. 2006 Sep;131(3):911-20
references.pmid: 16952559
references.citation: J Med Genet. 1971 Mar;8(1):107-12
references.pmid: 5098065
references.citation: Nat Rev Mol Cell Biol. 2007 Nov;8(11):880-93
references.pmid: 17955020
references.citation: Dev Biol. 2003 Jun 1;258(1):169-84
references.pmid: 12781691
references.citation: Development. 2010 Dec;137(24):4271-82
references.pmid: 21098568
references.citation: Physiol Rev. 2007 Jan;87(1):219-44
references.pmid: 17237346
references.citation: Am J Hum Genet. 2011 Apr 8;88(4):508-15
references.pmid: 21473986
references.citation: Bone. 2010 Apr;46(4):1146-55
references.pmid: 20053388
references.citation: Exp Cell Res. 2009 Sep 10;315(15):2648-57
references.pmid: 19559697
references.citation: Cytogenet Genome Res. 2007;117(1-4):231-9
references.pmid: 17675864
references.citation: Dev Dyn. 2011 May;240(5):1163-72
references.pmid: 21465618
references.citation: Development. 2009 Feb;136(4):655-64
references.pmid: 19144723
references.citation: J Morphol. 1951 Jan;88(1):49-92
references.pmid: 24539719
references.citation: Semin Liver Dis. 2003 May;23(2):195-200
references.pmid: 12800072
references.citation: Genes Dev. 2006 May 15;20(10):1365-77
references.pmid: 16702409
references.citation: Dev Dyn. 2004 Sep;231(1):57-71
references.pmid: 15305287
references.citation: Am J Physiol Gastrointest Liver Physiol. 2008 Mar;294(3):G595-8
references.pmid: 18218671
references.citation: Development. 2011 Aug;138(15):3261-72
references.pmid: 21750036
references.citation: Gastroenterology. 2011 Jun;140(7):1855-9, 1859.e1
references.pmid: 21515270
references.citation: Dev Biol. 2005 Nov 1;287(1):86-97
references.pmid: 16169547
references.citation: Liver Int. 2008 Mar;28(3):377-84
references.pmid: 17976156
references.citation: N Engl J Med. 2011 Apr 21;364(16):1533-43
references.pmid: 21506742
references.citation: Histochem Cell Biol. 2010 Oct;134(4):327-35
references.pmid: 20821230
references.citation: J Pediatr. 2001 Jul;139(1):130-3
references.pmid: 11445806
references.citation: Am J Med Genet. 2000 Feb 14;90(4):310-4
references.pmid: 10710229
references.citation: Am J Physiol Gastrointest Liver Physiol. 2006 Sep;291(3):G500-9
references.pmid: 16899714
references.citation: Gastroenterology. 2009 Oct;137(4):1478-1488.e8
references.pmid: 19577569
references.citation: Am J Hum Genet. 2011 Nov 11;89(5):634-43
references.pmid: 22019273
references.citation: Hepatology. 2010 May;51(5):1712-23
references.pmid: 20432255
references.citation: Am J Med Genet C Semin Med Genet. 2009 Nov 15;151C(4):296-306
references.pmid: 19876928
references.citation: Nat Genet. 1998 Sep;20(1):54-7
references.pmid: 9731531
references.citation: Nat Genet. 1998 Sep;20(1):58-61
references.pmid: 9731532
references.citation: Nature. 2003 Dec 4;426(6966):570-4
references.pmid: 14654843
references.citation: Methods Cell Biol. 2008;87:169-85
references.pmid: 18485297
references.citation: Am J Physiol Gastrointest Liver Physiol. 2006 May;290(5):G859-70
references.pmid: 16322088
references.citation: Development. 2001 Mar;128(6):871-81
references.pmid: 11222142
references.citation: Curr Biol. 1998 Sep 24;8(19):1083-6
references.pmid: 9768363
references.citation: Hepatology. 2011 Apr;53(4):1246-58
references.pmid: 21480329
references.citation: Development. 2006 May;133(9):1611-24
references.pmid: 16613830
references.citation: Dev Dyn. 2012 May;241(5):852-62
references.pmid: 22410853
references.citation: Nat Genet. 2007 Jun;39(6):727-9
references.pmid: 17468754
references.citation: Development. 2008 Apr;135(7):1365-76
references.pmid: 18305003
references.citation: Nat Rev Genet. 2010 May;11(5):331-44
references.pmid: 20395968
references.citation: Development. 1995 Oct;121(10):3163-74
references.pmid: 7588051
references.citation: Neonatology. 2011;99(3):231-40
references.pmid: 21071980
references.citation: Gastroenterology. 2013 May;144(5):1107-1115.e3
references.pmid: 23336978
references.citation: Am J Med Genet Suppl. 1987;3:211-20
references.pmid: 3130856
references.citation: Development. 1999 Jun;126(11):2397-407
references.pmid: 10225999
references.citation: BMC Biol. 2012 Dec 19;10:102
references.pmid: 23256866
references.citation: Differentiation. 2004 Sep;72(7):348-62
references.pmid: 15554946
references.citation: J Hepatol. 2012 May;56(5):1201-1203
references.pmid: 22133568
references.citation: Genes Dev. 1998 Oct 15;12(20):3156-61
references.pmid: 9784490
references.citation: J Hepatol. 2014 Jan;60(1):143-51
references.pmid: 23978713
references.citation: Am J Hum Genet. 2009 May;84(5):706-11
references.pmid: 19442771
references.citation: Semin Pediatr Neurol. 2009 Sep;16(3):143-54
references.pmid: 19778711
references.citation: J Histochem Cytochem. 2001 Dec;49(12):1593-604
references.pmid: 11724907
references.citation: Hum Mol Genet. 2012 Apr 15;21(8):1808-23
references.pmid: 22228095
references.citation: Hum Mol Genet. 2011 Apr 1;20(7):1306-14
references.pmid: 21227999
references.citation: Eur J Pediatr. 2010 Jan;169(1):77-88
references.pmid: 19430947
references.citation: Curr Biol. 2002 Nov 19;12(22):1965-9
references.pmid: 12445392