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

Heejung Moon, Jieun Song, Jeong Oh Shin, Hankyu Lee, Hong Kyung Kim, Jonathan T. Eggenschwiller, Jinwoong Bok, Hyuk Wan Ko

Research output: Contribution to journalArticle

26 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)8541-8546
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number23
DOIs
Publication statusPublished - 2014 Jun 10

Fingerprint

Hedgehogs
Cilia
Phosphotransferases
Knockout Mice
Cultured Cells
Embryonic Structures
Basal Bodies
Polydactyly
Phenotype
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Inborn Genetic Diseases
Cleft Palate
Missense Mutation
Mutant Proteins
Invertebrates
Hydrocephalus
Mitogen-Activated Protein Kinases
Protein Kinases
Mammals
Down-Regulation

All Science Journal Classification (ASJC) codes

  • General

Cite this

Moon, Heejung ; Song, Jieun ; Shin, Jeong Oh ; Lee, Hankyu ; Kim, Hong Kyung ; Eggenschwiller, Jonathan T. ; Bok, Jinwoong ; Ko, Hyuk Wan. / Intestinal cell kinase, aprotein associated with endocrine-cerebro- osteodysplasia syndrome,is a key regulator of cilia length and Hedgehog signaling. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 23. pp. 8541-8546.
@article{0f0d59a013894f7dab24d5ff708387e5,
title = "Intestinal cell kinase, aprotein associated with endocrine-cerebro- osteodysplasia syndrome,is a key regulator of cilia length and Hedgehog signaling",
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.",
author = "Heejung Moon and Jieun Song and Shin, {Jeong Oh} and Hankyu Lee and Kim, {Hong Kyung} and Eggenschwiller, {Jonathan T.} and Jinwoong Bok and Ko, {Hyuk Wan}",
year = "2014",
month = "6",
day = "10",
doi = "10.1073/pnas.1323161111",
language = "English",
volume = "111",
pages = "8541--8546",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "23",

}

Intestinal cell kinase, aprotein associated with endocrine-cerebro- osteodysplasia syndrome,is a key regulator of cilia length and Hedgehog signaling. / Moon, Heejung; Song, Jieun; Shin, Jeong Oh; Lee, Hankyu; Kim, Hong Kyung; Eggenschwiller, Jonathan T.; Bok, Jinwoong; Ko, Hyuk Wan.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 23, 10.06.2014, p. 8541-8546.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Intestinal cell kinase, aprotein associated with endocrine-cerebro- osteodysplasia syndrome,is a key regulator of cilia length and Hedgehog signaling

AU - Moon, Heejung

AU - Song, Jieun

AU - Shin, Jeong Oh

AU - Lee, Hankyu

AU - Kim, Hong Kyung

AU - Eggenschwiller, Jonathan T.

AU - Bok, Jinwoong

AU - Ko, Hyuk Wan

PY - 2014/6/10

Y1 - 2014/6/10

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84902215356&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84902215356&partnerID=8YFLogxK

U2 - 10.1073/pnas.1323161111

DO - 10.1073/pnas.1323161111

M3 - Article

VL - 111

SP - 8541

EP - 8546

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 23

ER -