Loss of the serine/threonine kinase fused results in postnatal growth defects and lethality due to progressive hydrocephalus
Loss of the serine/threonine kinase fused results in postnatal growth defects and lethality due to progressive hydrocephalus
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DOI：
10.1128/mcb.25.16.7054-7068.2005
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发表时间：
2005-08-01
影响因子：
5.3
通讯作者：
de Sauvage, FJ
中科院分区：
文献类型：
--
作者：
Merchant, M;Evangelista, M;de Sauvage, FJ
果蝇融合 (Fu) 激酶是 Hedgehog (Hh) 通路的一个组成部分，有助于促进 Hh 依赖性基因转录。 Fu 的脊椎动物同源物在体外 Hh 通路中发挥作用，表明 Fu 在进化上是保守的。我们已经生成了融合 (stk36) 敲除小鼠，以解决小鼠 Fu (mFu) 同源物的体内功能。融合基因敲除细胞发育正常，以孟德尔比例出生，但在两周内无法生长，表现出严重的生长迟缓，伴有交通性脑积水和早期死亡。该融合基因在室管膜细胞和脉络丛以及参与脑脊液 (CSF) 产生和循环的组织中高表达，表明 mFu 的缺失会破坏 CSF 稳态。同样，融合蛋白在鼻上皮中高度表达，其中融合蛋白敲除显示双侧化脓性鼻炎。在需要 Hh 信号传导的器官（四肢、面部、骨骼等）发育中未观察到明显缺陷。在融合敲除中，神经管中 Hh 对神经元细胞命运的规范是正常的，并且许多组织中 Hh 靶基因的诱导不受 mFu 损失的影响。此外，用 Sonic Hh 刺激融合敲除小脑颗粒细胞增殖，未发现 Hh 信号传递存在缺陷。这些结果表明，mFu 同源物不是胚胎发育过程中 Hh 信号传导所必需的，而是适当的出生后发育所必需的，可能是通过调节 CSF 稳态或纤毛功能来实现的。
The Drosophila Fused (Fu) kinase is an integral component of the Hedgehog (Hh) pathway that helps promote Hh-dependent gene transcription. Vertebrate homologues of Fu function in the Hh pathway in vitro, suggesting that Fu is evolutionarily conserved. We have generated fused (stk36) knockout mice to address the in vivo function of the mouse Fu (mFu) homologue. fused knockouts develop normally, being born in Mendelian ratios, but fail to thrive within 2 weeks, displaying profound growth retardation with communicating hydrocephalus and early mortality. The fused gene is expressed highly in ependymal cells and the choroid plexus, tissues involved in the production and circulation of cerebral spinal fluid (CSF), suggesting that loss of mFu disrupts CSF homeostasis. Similarly, fused is highly expressed in the nasal epithelium, where fused knockouts display bilateral suppurative rhinitis. No obvious defects were observed in the development of organs where Hh signaling is required (limbs, face, bones, etc.). Specification of neuronal cell fates by Hh in the neural tube was normal in fused knockouts, and induction of Hh target genes in numerous tissues is not affected by the loss of mFu. Furthermore, stimulation of fused knockout cerebellar granule cells to proliferate with Sonic Hh revealed no defect in Hh signal transmission. These results show that the mFu homologue is not required for Hh signaling during embryonic development but is required for proper postnatal development, possibly by regulating the CSF homeostasis or ciliary function.