Intestinal cell kinase, a protein associated with endocrine-cerebro-osteodysplasia syndrome, is a key regulator of cilia length and Hedgehog signaling
Intestinal cell kinase, a protein associated with endocrine-cerebro-osteodysplasia syndrome, is a key regulator of cilia length and Hedgehog signaling
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DOI：
10.1073/pnas.1323161111
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发表时间：
2014-06-10
影响因子：
11.1
通讯作者：
Ko, Hyuk Wan
中科院分区：
文献类型：
--
作者：
Moon, Heejung;Song, Jieun;Ko, Hyuk Wan
内分泌-脑-骨发育不良（ECO）综合征是一种隐性遗传性疾病，与内分泌、脑和骨骼系统的多种先天性缺陷相关，由丝裂原活化蛋白激酶样肠细胞激酶（ICK）基因的错义突变引起。在藻类和无脊椎动物中，ICK同源物分别参与鞭毛形成和纤毛发生。然而，目前尚不清楚ICK的这种作用是否在哺乳动物中是保守的，以及功能性ICK的缺乏如何导致人类ECO综合征的特征表型。在这里，我们产生了Ick基因敲除小鼠，以阐明ICK在哺乳动物发育中的确切作用，并研究ECO综合征的病理机制。Ick无效小鼠胚胎显示腭裂，脑积水，多指（趾）畸形和骨骼发育延迟，非常类似ECO综合征表型。在培养的细胞中，Ick的下调或激酶死亡或ECO综合征突变体ICK的过度表达导致初级纤毛的伸长和异常的Sonic hedgehog（Shh）信号传导。野生型ICK蛋白通常定位于近端区域的纤毛附近的基体，而激酶死亡ICK突变体蛋白积累在远端部分凸出的纤毛提示。与培养细胞中的这些观察结果一致，Ick敲除小鼠胚胎在肢体数字图案形成期间显示出细长的纤毛和减少的Shh信号传导。综上所述，这些结果表明ICK在控制纤毛长度中起着至关重要的作用，并且由功能性ICK缺乏引起的纤毛缺陷导致异常Shh信号传导，从而导致先天性疾病如ECO综合征。
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.