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Intestinal cell kinase, a protein associated with endocrine-cerebro-osteodysplasia syndrome, is a key regulator of cilia length and Hedgehog signaling

Authors
 Heejung Moon  ;  Jieun Song  ;  Jeong-Oh Shin  ;  Hankyu Lee  ;  Hong-Kyung Kim  ;  Jonathan T. Eggenschwiller  ;  Jinwoong Bok  ;  Hyuk Wan Ko 
Citation
 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol.111(23) : 8541-8546, 2014 
Journal Title
 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 
ISSN
 0027-8424 
Issue Date
2014
MeSH
Abnormalities, Multiple/genetics ; Abnormalities, Multiple/pathology* ; Animals ; Blotting, Western ; Body Patterning/genetics ; Body Patterning/physiology ; Cerebral Cortex/embryology ; Cerebral Cortex/pathology ; Cilia/genetics ; Cilia/metabolism* ; Embryo, Mammalian/abnormalities ; Embryo, Mammalian/metabolism ; Embryo, Mammalian/ultrastructure ; Endocrine System/embryology ; Endocrine System/pathology ; Hedgehog Proteins/genetics ; Hedgehog Proteins/metabolism* ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Microscopy, Confocal ; Microscopy, Electron ; Musculoskeletal System/embryology ; Musculoskeletal System/pathology ; NIH 3T3 Cells ; Protein-Serine-Threonine Kinases/genetics ; Protein-Serine-Threonine Kinases/metabolism* ; RNA Interference ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/genetics ; Signal Transduction/physiology* ; Syndrome
Keywords
Gli2 ; LF4 ; MRK ; Smoothened ; ciliopathy
Abstract
Endocrine-cerebro-osteodysplasia (ECO) syndrome is a recessive genetic disorder associated with multiple congenital defects in endocrine, cerebral, and skeletal systems that is caused by a missense mutation in the mitogen-activated protein kinase-like intestinal cell kinase (ICK) gene. In algae and invertebrates, ICK homologs are involved in flagellar formation and ciliogenesis, respectively. However, it is not clear whether this role of ICK is conserved in mammals and how a lack of functional ICK results in the characteristic phenotypes of human ECO syndrome. Here, we generated Ick knockout mice to elucidate the precise role of ICK in mammalian development and to examine the pathological mechanisms of ECO syndrome. Ick null mouse embryos displayed cleft palate, hydrocephalus, polydactyly, and delayed skeletal development, closely resembling ECO syndrome phenotypes. In cultured cells, down-regulation of Ick or overexpression of kinase-dead or ECO syndrome mutant ICK resulted in an elongation of primary cilia and abnormal Sonic hedgehog (Shh) signaling. Wild-type ICK proteins were generally localized in the proximal region of cilia near the basal bodies, whereas kinase-dead ICK mutant proteins accumulated in the distal part of bulged ciliary tips. Consistent with these observations in cultured cells, Ick knockout mouse embryos displayed elongated cilia and reduced Shh signaling during limb digit patterning. Taken together, these results indicate that ICK plays a crucial role in controlling ciliary length and that ciliary defects caused by a lack of functional ICK leads to abnormal Shh signaling, resulting in congenital disorders such as ECO syndrome.
Files in This Item:
T201402051.pdf Download
DOI
10.1073/pnas.1323161111
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Anatomy (해부학교실) > 1. Journal Papers
Yonsei Authors
Bok, Jin Woong(복진웅) ORCID logo https://orcid.org/0000-0003-1958-1872
Shin, Jeong Oh(신정오) ORCID logo https://orcid.org/0000-0002-6935-0936
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/99082
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