TableEdit

Friedland-Little, JM, Hoffmann, AD, Ocbina, PJ, Peterson, MA, Bosman, JD, Chen, Y, Cheng, SY, Anderson, KV and Moskowitz, IP (2011) A novel murine allele of Intraflagellar Transport Protein 172 causes a syndrome including VACTERL-like features with hydrocephalus. Hum. Mol. Genet. 20:3725-37

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.

PubMed PMC3168284 Online version:10.1093/hmg/ddr241

Alleles; Anal Canal/abnormalities; Anal Canal/embryology; Anal Canal/metabolism; Animals; Cilia/genetics; Cilia/metabolism; Disease Models, Animal; Esophagus/abnormalities; Esophagus/embryology; Esophagus/metabolism; Heart Defects, Congenital/embryology; Heart Defects, Congenital/genetics; Heart Defects, Congenital/metabolism; Hedgehog Proteins/genetics; Hedgehog Proteins/metabolism; Humans; Hydrocephalus/embryology; Hydrocephalus/genetics; Hydrocephalus/metabolism; Intracellular Signaling Peptides and Proteins/genetics; Intracellular Signaling Peptides and Proteins/metabolism; Kidney/abnormalities; Kidney/embryology; Kidney/metabolism; Limb Deformities, Congenital/embryology; Limb Deformities, Congenital/genetics; Limb Deformities, Congenital/metabolism; Mice/genetics; Mice/metabolism; Mice, Inbred C3H; Mice, Inbred C57BL; Mutagenesis; Mutation; Protein Transport; Signal Transduction/genetics; Spine/abnormalities; Spine/embryology; Spine/metabolism; Trachea/abnormalities; Trachea/embryology; Trachea/metabolism; Tumor Suppressor Proteins/genetics; Tumor Suppressor Proteins/metabolism