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Proc Natl Acad Sci U S A. 2014 Jun 10;111(23):8541-6. doi: 10.1073/pnas.1323161111. Epub 2014 May 22.

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

Author information

1
College of Pharmacy, Dongguk University-Seoul, Goyang, 410-820, Korea;
2
Department of Anatomy, BK21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, Korea; and.
3
Department of Genetics, University of Georgia, Athens, GA 30606.
4
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.
5
College of Pharmacy, Dongguk University-Seoul, Goyang, 410-820, Korea; kohw@dongguk.edu bokj@yuhs.ac.

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.

KEYWORDS:

Gli2; LF4; MRK; Smoothened; ciliopathy

PMID:
24853502
PMCID:
PMC4060650
DOI:
10.1073/pnas.1323161111
[Indexed for MEDLINE]
Free PMC Article

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