A novel murine allele of intraflagellar transport protein 172 causes a syndrome including VACTERL-like features with hydrocephalus Journal Article
| Authors: | Friedland-Little, J. M.; Hoffmann, A. D.; Ocbina, P. J. R.; Peterson, M. A.; Bosman, J. D.; Chen, Y.; Cheng, S. Y.; Anderson, K. V.; Moskowitz, I. P. |
| Article 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 Ift172avc1 and Ift172wim, 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. © The Author 2011. Published by Oxford University Press. All rights reserved. |
| Keywords: | signal transduction; controlled study; carrier protein; unclassified drug; gene mutation; mutation; clinical feature; dose response; nonhuman; animal cell; mouse; phenotype; animals; mice; allele; cell structure; embryo; sonic hedgehog protein; animal experiment; animal model; hedgehog proteins; alleles; in vivo study; in vitro study; wild type; mice, inbred c57bl; vertebrata; kidney; syndrome; intracellular signaling peptides and proteins; tumor suppressor proteins; spine; protein transport; murinae; fibroblast; disease models, animal; erinaceidae; eukaryotic flagellum; cilia; esophagus; mutagenesis; heart defects, congenital; null allele; intraflagellar transport protein 172; embryo cell; trachea; hydrocephalus; anal canal; mice, inbred c3h; axoneme; limb deformities, congenital; atrioventricular canal; syndrome vater; vacterl hydrocephalus syndrome |
| Journal Title: | Human Molecular Genetics |
| Volume: | 20 |
| Issue: | 19 |
| ISSN: | 0964-6906 |
| Publisher: | Oxford University Press |
| Date Published: | 2011-10-01 |
| Start Page: | 3725 |
| End Page: | 3737 |
| Language: | English |
| DOI: | 10.1093/hmg/ddr241 |
| PROVIDER: | scopus |
| PMCID: | PMC3168284 |
| PUBMED: | 21653639 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 3 October 2011" - "Art. No.: ddr241" - "CODEN: HMGEE" - "Source: Scopus" |
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