title: The graded response to Sonic Hedgehog depends on cilia architecture.
abstract: Several studies have linked cilia and Hedgehog signaling, but the precise roles of ciliary proteins in signal transduction remain enigmatic. Here we describe a mouse mutation, hennin (hnn), that causes coupled defects in cilia structure and Sonic hedgehog (Shh) signaling. The hnn mutant cilia are short with a specific defect in the structure of the ciliary axoneme, and the hnn neural tube shows a Shh-independent expansion of the domain of motor neuron progenitors. The hnn mutation is a null allele of Arl13b, a small GTPase of the Arf/Arl family, and the Arl13b protein is localized to cilia. Double mutant analysis indicates that Gli3 repressor activity is normal in hnn embryos, but Gli activators are constitutively active at low levels. Thus, normal structure of the ciliary axoneme is required for the cell to translate different levels of Shh ligand into differential regulation of the Gli transcription factors that implement Hedgehog signals.
authors.affiliation: Developmental Biology Program, Sloan-Kettering Institute, 1275 York Avenue, New York, NY 10021, USA.
authors.forename: Tamara
authors.initials: T
authors.lastname: Caspary
authors.forename: Christine E
authors.initials: CE
authors.lastname: Larkins
authors.forename: Kathryn V
authors.initials: KV
authors.lastname: Anderson
mesh_terms: D000483:Alleles; D000818:Animals; D019521:Body Patterning; D002923:Cilia / Q000378:metabolism* / Q000648:ultrastructure; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000648:ultrastructure; D005091:Exons / Q000235:genetics; D005124:Eye Abnormalities / Q000196:embryology; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D007438:Introns / Q000235:genetics; D008024:Ligands; D017880:Limb Deformities, Congenital / Q000196:embryology; D051379:Mice; D009154:Mutation / Q000235:genetics; D009436:Neural Tube Defects / Q000196:embryology; D015513:Oncogene Proteins / Q000378:metabolism; D000072079:Patched Receptors; D010641:Phenotype; D021381:Protein Transport; D011956:Receptors, Cell Surface / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D000072086:Smoothened Receptor; D015534:Trans-Activators / Q000378:metabolism; D000071676:Zinc Finger Protein GLI1
chemical_list: D003598:Cytoskeletal Proteins; D053823:Hedgehog Proteins; D008024:Ligands; D015513:Oncogene Proteins; D000072079:Patched Receptors; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C465570:Shh protein, mouse; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D015534:Trans-Activators; D000071676:Zinc Finger Protein GLI1