title: A novel ciliopathic skull defect arising from excess neural crest.
abstract: The skull is essential for protecting the brain from damage, and birth defects involving disorganization of skull bones are common. However, the developmental trajectories and molecular etiologies by which many craniofacial phenotypes arise remain poorly understood. Here, we report a novel skull defect in ciliopathic Fuz mutant mice in which only a single bone pair encases the forebrain, instead of the usual paired frontal and parietal bones. Through genetic lineage analysis, we show that this defect stems from a massive expansion of the neural crest-derived frontal bone. This expansion occurs at the expense of the mesodermally-derived parietal bones, which are either severely reduced or absent. A similar, though less severe, phenotype was observed in Gli3 mutant mice, consistent with a role for Gli3 in cilia-mediated signaling. Excess crest has also been shown to drive defective palate morphogenesis in ciliopathic mice, and that defect is ameliorated by reduction of Fgf8 gene dosage. Strikingly, skull defects in Fuz mutant mice are also rescued by loss of one allele of fgf8, suggesting a potential route to therapy. In sum, this work is significant for revealing a novel skull defect with a previously un-described developmental etiology and for suggesting a common developmental origin for skull and palate defects in ciliopathies.
authors.affiliation: Department of Molecular Biosciences, University of Texas at Austin, United States.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Tabler
authors.affiliation: Department of Molecular Biosciences, University of Texas at Austin, United States.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Rice
authors.affiliation: Department of Craniofacial Development and Stem Cell Biology, King's College London, UK. Electronic address: karen.liu@kcl.ac.uk.
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Liu
authors.affiliation: Department of Molecular Biosciences, University of Texas at Austin, United States. Electronic address: Wallingford@austin.utexas.edu.
authors.forename: John B
authors.initials: JB
authors.lastname: Wallingford
mesh_terms: D000818:Animals; D000072661:Ciliopathies / Q000235:genetics; D019465:Craniofacial Abnormalities / Q000196:embryology* / Q000235:genetics; D003598:Cytoskeletal Proteins; D051524:Fibroblast Growth Factor 8 / Q000235:genetics; D005624:Frontal Bone / Q000002:abnormalities* / Q000196:embryology; D018628:Gene Dosage / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D008648:Mesoderm / Q000196:embryology; D051379:Mice; D008822:Mice, Transgenic; D009024:Morphogenesis; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009432:Neural Crest / Q000196:embryology*; D010294:Parietal Bone / Q000002:abnormalities* / Q000196:embryology; D015398:Signal Transduction / Q000235:genetics; D012886:Skull / Q000002:abnormalities*; D000074290:Zinc Finger Protein Gli3
chemical_list: D003598:Cytoskeletal Proteins; C496457:Fgf8 protein, mouse; C544812:Fuz protein, mouse; C465571:Gli3 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D000074290:Zinc Finger Protein Gli3; D051524:Fibroblast Growth Factor 8
keywords: Calvaria; Cilia; Ciliopathy; Coronal suture; Craniofacial; Craniosynostosis; Fgf8; Fuz; Greig cephalopolysyndactyly; Mesp1; Morphogenesis; Mouse; Neural crest; Skull; Wnt1