title: A novel murine allele of Intraflagellar Transport Protein 172 causes a syndrome including VACTERL-like features with hydrocephalus.
abstract: The primary cilium is emerging as a crucial regulator of signaling pathways central to vertebrate development and human disease. We identified atrioventricular canal 1 (avc1), a mouse mutation that caused VACTERL association with hydrocephalus, or VACTERL-H. We showed that avc1 is a hypomorphic mutation of intraflagellar transport protein 172 (Ift172), required for ciliogenesis and Hedgehog (Hh) signaling. Phenotypically, avc1 caused VACTERL-H but not abnormalities in left-right (L-R) axis formation. Avc1 resulted in structural cilia defects, including truncated cilia in vivo and in vitro. We observed a dose-dependent requirement for Ift172 in ciliogenesis using an allelic series generated with Ift172(avc1) and Ift172(wim), an Ift172 null allele: cilia were present on 42% of avc1 mouse embryonic fibroblast (MEF) and 28% of avc1/wim MEFs, in contrast to >90% of wild-type MEFs. Furthermore, quantitative cilium length analysis identified two specific cilium populations in mutant MEFS: a normal population with normal IFT and a truncated population, 50% of normal length, with disrupted IFT. Cells from wild-type embryos had predominantly full-length cilia, avc1 embryos, with Hh signaling abnormalities but not L-R abnormalities, had cilia equally divided between full-length and truncated, and avc1/wim embryos, with both Hh signaling and L-R abnormalities, were primarily truncated. Truncated Ift172 mutant cilia showed defects of the distal ciliary axoneme, including disrupted IFT88 localization and Hh-dependent Gli2 localization. We propose a model in which mutation of Ift172 results in a specific class of abnormal cilia, causing disrupted Hh signaling while maintaining L-R axis determination, and resulting in the VACTERL-H phenotype.
authors.affiliation: Department of Pediatrics, The University of Chicago, 900 East 57th Street, Chicago, IL 60637, USA.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Friedland-Little
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Hoffmann
authors.forename: Polloneal Jymmiel R
authors.initials: PJ
authors.lastname: Ocbina
authors.forename: Mike A
authors.initials: MA
authors.lastname: Peterson
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Bosman
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: Steven Y
authors.initials: SY
authors.lastname: Cheng
authors.forename: Kathryn V
authors.initials: KV
authors.lastname: Anderson
authors.forename: Ivan P
authors.initials: IP
authors.lastname: Moskowitz
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000483:Alleles; D001003:Anal Canal / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism; D000818:Animals; D002923:Cilia / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins; D004195:Disease Models, Animal; D004947:Esophagus / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism; D006330:Heart Defects, Congenital / Q000196:embryology / Q000235:genetics* / Q000378:metabolism; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006849:Hydrocephalus / Q000196:embryology / Q000235:genetics* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D007668:Kidney / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism; D017880:Limb Deformities, Congenital / Q000196:embryology / Q000235:genetics* / Q000378:metabolism; D051379:Mice / Q000235:genetics* / Q000378:metabolism; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016296:Mutagenesis; D009154:Mutation; D021381:Protein Transport; D015398:Signal Transduction / Q000235:genetics; D013131:Spine / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism; D014132:Trachea / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D053823:Hedgehog Proteins; C479520:Ift172 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; C490898:Tg737Rpw protein, mouse; D025521:Tumor Suppressor Proteins