Intestinal cell kinase, a protein associated with endocrine-cerebro-osteodysplasia syndrome, is a key regulator of cilia length and Hedgehog signaling.
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.
College of Pharmacy, Dongguk University-Seoul, Goyang, 410-820, Korea;
Heejung
H
Moon
College of Pharmacy, Dongguk University-Seoul, Goyang, 410-820, Korea;
Jieun
J
Song
Department of Anatomy, BK21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, Korea; and.
Jeong-Oh
JO
Shin
College of Pharmacy, Dongguk University-Seoul, Goyang, 410-820, Korea;
Hankyu
H
Lee
Department of Anatomy, BK21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, Korea; and.
Hong-Kyung
HK
Kim
Department of Genetics, University of Georgia, Athens, GA 30606.
Jonathan T
JT
Eggenschwiller
Department of Anatomy, BK21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, Korea; and kohw@dongguk.edu bokj@yuhs.ac.
Jinwoong
J
Bok
College of Pharmacy, Dongguk University-Seoul, Goyang, 410-820, Korea; kohw@dongguk.edu bokj@yuhs.ac.
Hyuk Wan
HW
Ko
D000015:Abnormalities, Multiple / Q000235:genetics / Q000473:pathology*; D000818:Animals; D015153:Blotting, Western; D019521:Body Patterning / Q000235:genetics / Q000502:physiology; D002540:Cerebral Cortex / Q000196:embryology / Q000473:pathology; D002923:Cilia / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000378:metabolism / Q000648:ultrastructure; D004703:Endocrine System / Q000196:embryology / Q000473:pathology; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D009141:Musculoskeletal System / Q000196:embryology / Q000473:pathology; D041681:NIH 3T3 Cells; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013577:Syndrome
D053823:Hedgehog Proteins; C465570:Shh protein, mouse; C000591805:Cilk1 protein, mouse; D017346:Protein Serine-Threonine Kinases
Gli2; LF4; MRK; Smoothened; ciliopathy