title: Intraflagellar transport 88 (IFT88) is crucial for craniofacial development in mice and is a candidate gene for human cleft lip and palate.
abstract: Ciliopathies are pleiotropic human diseases resulting from defects of the primary cilium, and these patients often have cleft lip and palate. IFT88 is required for the assembly and function of the primary cilia, which mediate the activity of key developmental signaling pathways. Through whole exome sequencing of a family of three affected siblings with isolated cleft lip and palate, we discovered that they share a novel missense mutation in IFT88 (c.915G > C, p.E305D), suggesting this gene should be considered a candidate for isolated orofacial clefting. In order to evaluate the function of IFT88 in regulating craniofacial development, we generated Wnt1-Cre;Ift88fl/fl mice to eliminate Ift88 specifically in cranial neural crest (CNC) cells. Wnt1-Cre;Ift88fl/flpups died at birth due to severe craniofacial defects including bilateral cleft lip and palate and tongue agenesis, following the loss of the primary cilia in the CNC-derived palatal mesenchyme. Loss of Ift88 also resulted in a decrease in neural crest cell proliferation during early stages of palatogenesis as well as a downregulation of the Shh signaling pathway in the palatal mesenchyme. Importantly, Osr2KI-Cre;Ift88fl/flmice, in which Ift88 is lost specifically in the palatal mesenchyme, exhibit isolated cleft palate. Taken together, our results demonstrate that IFT88 has a highly conserved function within the primary cilia of the CNC-derived mesenchyme in the lip and palate region in mice and is a strong candidate as an orofacial clefting gene in humans.
authors.affiliation: Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA.|Department of Cariology and Endodontology, Peking University School and Hospital of Stomatology, Beijing 100081, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Tian
authors.affiliation: Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Jifan
authors.initials: J
authors.lastname: Feng
authors.affiliation: Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA.|Molecular Laboratory for Gene Therapy and Tooth Regeneration, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing 100050, China.
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Li
authors.affiliation: Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Thach-Vu
authors.initials: TV
authors.lastname: Ho
authors.affiliation: Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Department of Prosthodontics, Peking University School and Hospital of Stomatology, Beijing 100081, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Division of Plastic and Maxillofacial Surgery, Children's Hospital Los Angeles, Los Angeles, CA, USA.
authors.forename: Frederick
authors.initials: F
authors.lastname: Brindopke
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Jane C
authors.initials: JC
authors.lastname: Figueiredo
authors.affiliation: Division of Plastic and Maxillofacial Surgery, Children's Hospital Los Angeles, Los Angeles, CA, USA.
authors.forename: William
authors.initials: W
authors.lastname: Magee
authors.affiliation: Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA.|Center for Personalized Medicine, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.|Department of Pathology & Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Sanchez-Lara
authors.affiliation: Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Chai
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D002971:Cleft Lip / Q000235:genetics* / Q000473:pathology; D047108:Embryonic Development / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008648:Mesoderm / Q000254:growth & development / Q000473:pathology; D051379:Mice; D009432:Neural Crest / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D010159:Palate / Q000254:growth & development / Q000473:pathology; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics*; D051155:Wnt1 Protein / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C490898:Tg737Rpw protein, mouse; D025521:Tumor Suppressor Proteins; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse