Identification of cis-element regulating expression of the mouse Fgf10 gene during inner ear development
Identification of cis-element regulating expression of the mouse Fgf10 gene during inner ear development
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DOI：
10.1002/dvdy.20319
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发表时间：
2005-05-01
影响因子：
2.5
通讯作者：
Nohno, T
中科院分区：
文献类型：
--
作者：
Ohuchi, H;Yasue, A;Nohno, T
成纤维细胞生长因子(成纤维细胞生长因子)信号对耳朵的诱导和生长至关重要，耳朵是一种涉及密切组织相互作用的感官器官。在这里，我们报告了Fgf10缺失耳的异常，并鉴定了一个指导Fgf10基因表达的顺式调控元件。在Fgf10缺失的内耳中，我们发现半规管、前庭和耳蜗区的初始发育大致正常，之后出现半规管/脊和前庭发育的异常。突变的半圆形视盘在围产期仍未形成管状结构。为了阐明Fgf10在内耳发育过程中的表达调控，我们分离了Fgf10 5‘上游区6.6kb的片段，并利用LacZ报告系统检测了其在转基因小鼠中的转录活性。通过将小鼠的6.6kb片段与人和鸡的Fgf10的相应序列进行比较，我们发现了一个0.4kb的增强子序列，该序列驱动Fgf10在发育中的内耳表达。除了POU结构域因子(例如Brn3)、锌指转录因子(例如GATA结合因子)、Tcf/Lef-1和沙拉相互作用蛋白外，增强子序列还具有许多含有同源结构域的蛋白质(例如Prx、Hox、Nkx)的基序。因此，FGF10信号对于确定耳室的特性是可有可无的，但对于掏空半圆形视盘是必需的。此外，对Fgf10可能的内耳增强子的分析揭示了Fgf10在内耳发育过程中通过多种转录因子和信号通路进行复杂的调控。(C)2005年Wiley-Liss，Inc.
Fibroblast growth factor (FGF) signaling is crucial for the induction and growth of the ear, a sensory organ that involves intimate tissue interactions. Here, we report the abnormality of Fgf10 null ear and the identification of a cis-regulatory element directing otic expression of Fgf10. In Fgf10 null inner ears, we found that the initial development of semicircular, vestibular, and cochlear divisions is roughly normal, after which there are abnormalities of semicircular canal/cristae and vestibular development. The mutant semicircular disks remain without canal formation by the perinatal stage. To elucidate regulation of the Fgf10 expression during inner ear development, we isolated a 6.6-kb fragment of its 5'-upstream region and examined its transcriptional activity with transgenic mice, using a lacZ-reporter system. From comparison of the mouse sequences of the 6.6-kb fragment with corresponding sequences of the human and chicken Fgf10, we identified a 0.4-kb enhancer sequence that drives Fgf10 expression in the developing inner ear. The enhancer sequences have motifs for many homeodomain-containing proteins (e.g., Prx, Hox, Nkx), in addition to POU-domain factors (e.g., Brn3), zinc-finger transcription factors (e.g., GATA-binding factors), TCF/LEF-1, and a SALAD-interacting protein. Thus, FGF10 signaling is dispensable for specification of otic compartment identity but is required for hollowing the semicircular disk. Furthermore, the analysis of a putative inner ear enhancer of Fgf10 has disclosed a complicated regulation of Fgf10 during inner ear development by numerous transcription factors and signaling pathways. (c) 2005 Wiley-Liss, Inc.