title: An essential role of intestinal cell kinase in lung development is linked to the perinatal lethality of human ECO syndrome.
abstract: Human endocrine-cerebro-osteodysplasia (ECO) syndrome, caused by the loss-of-function mutation R272Q in the intestinal cell kinase (ICK) gene, is a neonatal-lethal developmental disorder. To elucidate the molecular basis of ECO syndrome, we constructed an Ick R272Q knock-in mouse model that recapitulates ECO pathological phenotypes. Newborns bearing Ick R272Q homozygous mutations die at birth due to respiratory distress. Ick mutant lungs exhibit not only impaired branching morphogenesis associated with reduced mesenchymal proliferation but also significant airspace deficiency in primitive alveoli concomitant with abnormal interstitial mesenchymal differentiation. ICK dysfunction induces elongated primary cilia and perturbs ciliary Hedgehog signaling and autophagy during lung sacculation. Our study identifies an essential role for ICK in lung development and advances the mechanistic understanding of ECO syndrome.
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA, USA.|The Gastrointestinal Surgery Center, Tongji Hospital, Huazhong University of Science & Technology, Hubei, China.
authors.forename: Yixin
authors.initials: Y
authors.lastname: Tong
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA, USA.
authors.forename: So Hyun
authors.initials: SH
authors.lastname: Park
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA, USA.
authors.forename: Di
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, USA.
authors.forename: Wenhao
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, USA.
authors.forename: Stacey J
authors.initials: SJ
authors.lastname: Guillot
authors.affiliation: Department of Orthopaedic Surgery, University of Virginia, Charlottesville, VA, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Jin
authors.affiliation: Department of Orthopaedic Surgery, University of Virginia, Charlottesville, VA, USA.
authors.forename: Xudong
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Cell Biology, University of Virginia, Charlottesville, VA, USA.
authors.forename: Yalin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Departments of Pathology and Cell Biology, Columbia University, New York, NY, USA.
authors.forename: Chyuan-Sheng
authors.initials: CS
authors.lastname: Lin
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Fu
mesh_terms: D000015:Abnormalities, Multiple / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000002:abnormalities / Q000378:metabolism; D002923:Cilia / Q000378:metabolism; D004195:Disease Models, Animal; D004703:Endocrine System / Q000002:abnormalities / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008168:Lung / Q000196:embryology / Q000201:enzymology / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009139:Musculoskeletal Abnormalities / Q000235:genetics; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013577:Syndrome
chemical_list: D053823:Hedgehog Proteins; C000591805:Cilk1 protein, mouse; D017346:Protein Serine-Threonine Kinases
keywords: Hedgehog signaling; autophagy; endocrine-cerebro-osteodysplasia syndrome; intestinal cell kinase; lung development; primary cilium