Cauli: a mouse strain with an Ift140 mutation that results in a skeletal ciliopathy modelling Jeune syndrome

• Published in: PLoS genetics Vol. 9; no. 8; p. e1003746
• Main Authors: Miller, Kerry A, Ah-Cann, Casey J, Welfare, Megan F, Tan, Tiong Y, Pope, Kate, Caruana, Georgina, Freckmann, Mary-Louise, Savarirayan, Ravi, Bertram, John F, Dobbie, Michael S, Bateman, John F, Farlie, Peter G
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.08.2013; Public Library of Science (PLoS)
• Subjects: Animals; Carrier Proteins - genetics; Cell Communication - genetics; Cell Polarity; Cilia - genetics; Cilia - pathology; Cilia and ciliary motion; Cytoplasm; Defects; Disease Models, Animal; Ellis-Van Creveld Syndrome - genetics; Ellis-Van Creveld Syndrome - pathology; Embryonic Development - genetics; Gene mutations; Genetic aspects; Genetic disorders; Genotype & phenotype; Health aspects; Hedgehog Proteins - genetics; Humans; Mice; Mutation; Physiological aspects; Proteins; Scholarships & fellowships; Signal Transduction; Australia
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1003746

Cilia are architecturally complex organelles that protrude from the cell membrane and have signalling, sensory and motility functions that are central to normal tissue development and homeostasis. There are two broad categories of cilia; motile and non-motile, or primary, cilia. The central role of primary cilia in health and disease has become prominent in the past decade with the recognition of a number of human syndromes that result from defects in the formation or function of primary cilia. This rapidly growing class of conditions, now known as ciliopathies, impact the development of a diverse range of tissues including the neural axis, craniofacial structures, skeleton, kidneys, eyes and lungs. The broad impact of cilia dysfunction on development reflects the pivotal position of the primary cilia within a signalling nexus involving a growing number of growth factor systems including Hedgehog, Pdgf, Fgf, Hippo, Notch and both canonical Wnt and planar cell polarity. We have identified a novel ENU mutant allele of Ift140, which causes a mid-gestation embryonic lethal phenotype in homozygous mutant mice. Mutant embryos exhibit a range of phenotypes including exencephaly and spina bifida, craniofacial dysmorphism, digit anomalies, cardiac anomalies and somite patterning defects. A number of these phenotypes can be attributed to alterations in Hedgehog signalling, although additional signalling systems are also likely to be involved. We also report the identification of a homozygous recessive mutation in IFT140 in a Jeune syndrome patient. This ENU-induced Jeune syndrome model will be useful in delineating the origins of dysmorphology in human ciliopathies.