同源域转录因子Isl1对小鼠幽门发育的调节功能和相关机理
摘要
已有的研究报道,同源域转录因子Isl1在胚胎期小鼠胃的间质和上皮细胞中表达,但Isll在幽门发育过程中的时空表达模式、功能和作用机理尚未有系统的研究。因此,本研究利用原位杂交(in situ hybridization,ISH)、实时定量PCR (real-time quantitative PCR, RT-qPCR)和免疫组织化学(immunohistochemistry, IHC)等方法系统分析Isl1在胃幽门发育过程中的表达变化；利用Isl1诱导敲除小鼠模型研究Isl1在幽门发育的功能；最后通过染色质免疫共沉淀(Chromatin immunoprecipitation, ChIP)、双荧光素酶检测系统和凝胶阻滞(electrophoretic mobility shift assays, EMSA)方法研究Isl1调节幽门发育的信号通路和机理。主要的研究结果如下：
1. RT-qPCR结果显示,Isll mRNA在小鼠E13.5胃中的表达量最高,E14.5急剧下降,但从E14.5到成年期无显著性变化；原位杂交和免疫组织化学结果显示,Isl1的表达局限于胃幽门部的肌肉层。
2. Isl1和a-SMA免疫荧光双染结果显示,Isll阳性细胞中表达a-SMA的细胞比例逐渐升高,并在人肥厚性幽门狭窄的病例组织中检测到Isl1表达。这些结果推测Isl1可能参与幽门肌肉的形成。
3. Tamoxifen诱导Isll敲除小鼠表现为Isll第四个外显子的缺失。蛋白质印迹和免疫荧光结果显示诱导Isll敲除(Isl1MCM/Del)小鼠的蛋白表达水平与野生型(Isl1F/+)小鼠相比明显变弱。这些证据表明tamoxifen高效诱导IslIMCM/Del小鼠敲除Isl1。
4.敲除Isl1对幽门上皮和神经的发育没有影响,但会导致幽门背部的外侧纵行肌(outer longitudinal muscle, OLM)缺失。
5. RT-qPCR结果显示,敲除Isll明显下调E14.5和E18.5小鼠胚胎胃中Nkx2.5、Gata3和Gremlin mRNA表达；全胚原位杂交结果显示,敲除Isll可使Nkx2.5、Gata3和Gremlin阳性信号变弱,其中Gata3mRNA降低70%左右。
6.免疫荧光双染结果证明Isl1和Gata3在幽门肌肉细胞中共表达。此外,ChIP结果表明Isll能够分别与启动子Gata3-P1和Gata3-P6序列结合。
7.双荧光素酶活性检测结果显示,Isl1激活Gata3-P1-WT (wild type, WT)区域的启动子活性,但对Gato3-P1-MT (mutant type, MT)、Gata3-P6-WT、Gata3-P6-MT和pGL3.0-basic启动子活性没有影响。
8. Gata3-P1区域包含3个ATTA结合位点,EMSA结果显示Isll (?)(?)够有效结合到第1和3位点。这些数据表明Isl1可以直接调节Gata3转录。
综上所述,LIM同源域蛋白转录因子Isll在幽门肌肉细胞中高表达,并且通过直接结合Gata3来调节幽门背部外侧纵行肌的发育。此外,这些研究结果提示Isll的表达可能与肥厚性幽门狭窄有关。
A recent report has shown that Isll is expressed in the mesenchyme and epithelium of the embryonic stomach in mice. However, it is unclear that regarding its spatiotemporal expression, functions and the related mechanisms in the pyloric development. First, we analyze Isl1expression in different developmental stages of the mouse pylorus by in situ hybridization (ISH), real-time quantitative PCR (RT-qPCR) and immunohistochemistry (IHC). Secondly, we identified the Isll biological functions in pyloric development utilizing an inducible Isl1knockout mouse model. Finally, we further study the signaling pathways and molecular mechanisms of Isl1in the pyloric development using chromatin immunoprecipitation (ChIP), dual luciferase vector and electrophoretic mobility shift assays (EMSA) methods. The most important results are as follows:
1. RT-qPCR results showed that Isll mRNA reached the highest level at E13.5, followed by a sharp decline at E14.5and had no significant changes into adulthood. ISH and IHC results demonstrated that Isl1was localized to the smooth muscle layer of the pylorus.
2. Isll and α-SMA double immunofluorescence results showed that the proportion of Isll positive cells expressing α-SMA gradually increased. Meantime, Isll was expressed in human pylorus with the hypertrophic pyloric stenosis. These results suggested that Isll may participate in the muscle formation of pylorus.
3. Tamoxifen inducible Isll knockout mice exhibited the deletion of exon4. Western blot and immunofluorescence results showed that Isl1protein levels in embryonic stomach of Isl1MCM/Del mice were significantly lower than those in wild type (Isl1F/+) mice. These collective data showed that Isl1expression was efficiently mutated in the IsllMCM/Del mice.
4. Isl1deficiency had no significant effect on epithelium and nerve development, but led to nearly complete absence of the dorsal pyloric outer longitudinal muscle (OLM) layer.
5. RT-qPCR results showed that Isll knockout down-regulated Nkx2.5, Gata3and Gremlin mRNA expression in the embryonic stomach both at E14.5and E18.5. Whole-mount ISH results showed that the ISH signals of aforementioned genes were much weaker in the Isl1MCM/Del mouse stomach than in Isl1F/+at E14.5. Gata3mRNA levels decreased about70%at both examined stages.
6. Double immunofluorescence results showed that Isll and Gata3were co-expressed in the pyloric smooth muscle cells. In addition, Gata3P1and P6regions were occupied by Isll protein through ChIP.
7. Dual-luciferase reporter assay showed that Isll enhanced the activity of the Gato3-P1-WT (wild type, WT) luciferase reporter, but Isl1did not affect luciferase activities of Gata3-P1-MT (mutant type, MT), Gata3-P6-WT, Gata3-P6-MT and pGL3.0-basic.
8. Gata3-P1promoter region includes three putative ATTA binding sites, and EMSA assay showed that Isll efficiently bound to oligonucleotides representing number1and number3sites. These collective data strongly showed that Isl1was a direct regulator of Gata3transcription.
Taken together, LIM homeodomain (LIM-HD) transcription factor Isl1was strongly expressed in the smooth muscle cells of pylorus, and involved in regulating dorsal pyloric OLM development via directly targeting Gata3. In addition, these findings suggested that Isl1may be related to hypertrophic pyloric stenosis.
1. RT-qPCR结果显示,Isll mRNA在小鼠E13.5胃中的表达量最高,E14.5急剧下降,但从E14.5到成年期无显著性变化；原位杂交和免疫组织化学结果显示,Isl1的表达局限于胃幽门部的肌肉层。
2. Isl1和a-SMA免疫荧光双染结果显示,Isll阳性细胞中表达a-SMA的细胞比例逐渐升高,并在人肥厚性幽门狭窄的病例组织中检测到Isl1表达。这些结果推测Isl1可能参与幽门肌肉的形成。
3. Tamoxifen诱导Isll敲除小鼠表现为Isll第四个外显子的缺失。蛋白质印迹和免疫荧光结果显示诱导Isll敲除(Isl1MCM/Del)小鼠的蛋白表达水平与野生型(Isl1F/+)小鼠相比明显变弱。这些证据表明tamoxifen高效诱导IslIMCM/Del小鼠敲除Isl1。
4.敲除Isl1对幽门上皮和神经的发育没有影响,但会导致幽门背部的外侧纵行肌(outer longitudinal muscle, OLM)缺失。
5. RT-qPCR结果显示,敲除Isll明显下调E14.5和E18.5小鼠胚胎胃中Nkx2.5、Gata3和Gremlin mRNA表达；全胚原位杂交结果显示,敲除Isll可使Nkx2.5、Gata3和Gremlin阳性信号变弱,其中Gata3mRNA降低70%左右。
6.免疫荧光双染结果证明Isl1和Gata3在幽门肌肉细胞中共表达。此外,ChIP结果表明Isll能够分别与启动子Gata3-P1和Gata3-P6序列结合。
7.双荧光素酶活性检测结果显示,Isl1激活Gata3-P1-WT (wild type, WT)区域的启动子活性,但对Gato3-P1-MT (mutant type, MT)、Gata3-P6-WT、Gata3-P6-MT和pGL3.0-basic启动子活性没有影响。
8. Gata3-P1区域包含3个ATTA结合位点,EMSA结果显示Isll (?)(?)够有效结合到第1和3位点。这些数据表明Isl1可以直接调节Gata3转录。
综上所述,LIM同源域蛋白转录因子Isll在幽门肌肉细胞中高表达,并且通过直接结合Gata3来调节幽门背部外侧纵行肌的发育。此外,这些研究结果提示Isll的表达可能与肥厚性幽门狭窄有关。
A recent report has shown that Isll is expressed in the mesenchyme and epithelium of the embryonic stomach in mice. However, it is unclear that regarding its spatiotemporal expression, functions and the related mechanisms in the pyloric development. First, we analyze Isl1expression in different developmental stages of the mouse pylorus by in situ hybridization (ISH), real-time quantitative PCR (RT-qPCR) and immunohistochemistry (IHC). Secondly, we identified the Isll biological functions in pyloric development utilizing an inducible Isl1knockout mouse model. Finally, we further study the signaling pathways and molecular mechanisms of Isl1in the pyloric development using chromatin immunoprecipitation (ChIP), dual luciferase vector and electrophoretic mobility shift assays (EMSA) methods. The most important results are as follows:
1. RT-qPCR results showed that Isll mRNA reached the highest level at E13.5, followed by a sharp decline at E14.5and had no significant changes into adulthood. ISH and IHC results demonstrated that Isl1was localized to the smooth muscle layer of the pylorus.
2. Isll and α-SMA double immunofluorescence results showed that the proportion of Isll positive cells expressing α-SMA gradually increased. Meantime, Isll was expressed in human pylorus with the hypertrophic pyloric stenosis. These results suggested that Isll may participate in the muscle formation of pylorus.
3. Tamoxifen inducible Isll knockout mice exhibited the deletion of exon4. Western blot and immunofluorescence results showed that Isl1protein levels in embryonic stomach of Isl1MCM/Del mice were significantly lower than those in wild type (Isl1F/+) mice. These collective data showed that Isl1expression was efficiently mutated in the IsllMCM/Del mice.
4. Isl1deficiency had no significant effect on epithelium and nerve development, but led to nearly complete absence of the dorsal pyloric outer longitudinal muscle (OLM) layer.
5. RT-qPCR results showed that Isll knockout down-regulated Nkx2.5, Gata3and Gremlin mRNA expression in the embryonic stomach both at E14.5and E18.5. Whole-mount ISH results showed that the ISH signals of aforementioned genes were much weaker in the Isl1MCM/Del mouse stomach than in Isl1F/+at E14.5. Gata3mRNA levels decreased about70%at both examined stages.
6. Double immunofluorescence results showed that Isll and Gata3were co-expressed in the pyloric smooth muscle cells. In addition, Gata3P1and P6regions were occupied by Isll protein through ChIP.
7. Dual-luciferase reporter assay showed that Isll enhanced the activity of the Gato3-P1-WT (wild type, WT) luciferase reporter, but Isl1did not affect luciferase activities of Gata3-P1-MT (mutant type, MT), Gata3-P6-WT, Gata3-P6-MT and pGL3.0-basic.
8. Gata3-P1promoter region includes three putative ATTA binding sites, and EMSA assay showed that Isll efficiently bound to oligonucleotides representing number1and number3sites. These collective data strongly showed that Isl1was a direct regulator of Gata3transcription.
Taken together, LIM homeodomain (LIM-HD) transcription factor Isl1was strongly expressed in the smooth muscle cells of pylorus, and involved in regulating dorsal pyloric OLM development via directly targeting Gata3. In addition, these findings suggested that Isl1may be related to hypertrophic pyloric stenosis.
引文
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