Fuz Mutant Mice Reveal Shared Mechanisms between Ciliopathies and FGF-Related Syndromes

• Published in: Developmental cell 2013-06, Vol.25 (6), p.623-635
• Main Authors: Tabler, Jacqueline M., Barrell, William B., Szabo-Rogers, Heather L., Healy, Christopher, Yeung, Yvonne, Perdiguero, Elisa Gomez, Schulz, Christian, Yannakoudakis, Basil Z., Mesbahi, Aida, Wlodarczyk, Bogdan, Geissmann, Frederic, Finnell, Richard H., Wallingford, John B., Liu, Karen J.
• Format: Article
• Language: English
• Subjects: Animals; Bardet-Biedl Syndrome - genetics; Bardet-Biedl Syndrome - pathology; Cell Movement - physiology; Ciliary Motility Disorders - genetics; Ciliary Motility Disorders - pathology; Craniofacial Abnormalities - genetics; Craniofacial Abnormalities - pathology; Cytoskeletal Proteins; Development Biology; Disease Models, Animal; Fibroblast Growth Factor 8 - genetics; Fibroblast Growth Factor 8 - metabolism; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Life Sciences; Maxilla - abnormalities; Mice; Mice, Mutant Strains; Neural Crest - abnormalities; Orofaciodigital Syndromes - genetics; Orofaciodigital Syndromes - pathology; Palate - abnormalities; Phenotype; Zinc Finger Protein GLI1
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2013.05.021

Ciliopathies are a broad class of human disorders with craniofacial dysmorphology as a common feature. Among these is high arched palate, a condition that affects speech and quality of life. Using the ciliopathic Fuz mutant mouse, we find that high arched palate does not, as commonly suggested, arise from midface hypoplasia. Rather, increased neural crest expands the maxillary primordia. In Fuz mutants, this phenotype stems from dysregulated Gli processing, which in turn results in excessive craniofacial Fgf8 gene expression. Accordingly, genetic reduction of Fgf8 ameliorates the maxillary phenotypes. Similar phenotypes result from mutation of oral-facial-digital syndrome 1 (Ofd1), suggesting that aberrant transcription of Fgf8 is a common feature of ciliopathies. High arched palate is also a prevalent feature of fibroblast growth factor (FGF) hyperactivation syndromes. Thus, our findings elucidate the etiology for a common craniofacial anomaly and identify links between two classes of human disease: FGF-hyperactivation syndromes and ciliopathies. •A genetic model for high arched palate, commonly seen in human craniofacial syndromes•In ciliopathic mice, Fgf8 overexpression leads to cranial neural crest hyperplasia•Enlargement of the maxillary primordia underlies high arched palate in Fuz mutants•An etiological link between ciliopathies and FGF-hyperactivation syndromes High arched palate is common to many human disorders, including ciliopathies and craniosynostosis syndromes. Tabler et al. develop and analyze a genetic model of high arched palate; they conclude that embryonic changes in neural crest and fibroblast growth factor signaling underlie this unusual phenotype.