IHH和FGF8在脊椎动物肢翼远端骨骼元件发育中的功能研究
摘要
1903年,Farabee报道了第一例符合孟德尔遗传规律的人类常染色体显性遗传性状,即一种指(趾)畸形遗传病。1951年,Bell将该遗传病归为A1型短指(趾)症,其主要特征是中间指(趾)节缩短或缺失。2001年,我们实验室的高波等人报道了Ihh基因内的杂合错义突变导致了A1型短指(趾)症。在本课题中,我们分析了造成A1型短指(趾)症的三个突变体,并探索了指(趾)形成的信号调控机制。
我们从体外诱导和体内诱导两个方面研究了Ihh的信号活性。在体外实验中,我们比较了野生型Ihh和三个突变型Ihh之间诱导效应的差异。用表达全长Ihh的质粒来诱导C3H10T1/2细胞,结果显示突变型Ihh的诱导效应明显减弱,但没有完全丧失。用原核表达并纯化的N-Ihh蛋白诱导C3H10T1/2细胞,结果与质粒诱导相仿。在体内实验中,我们将野生型N-Ihh蛋白导入到鸡胚指间区域,导致间叶细胞内Ihh信号通路活性上升和倒数第二指节变长,甚至长出额外的指节。Ihh在鸡胚中的表达模式分析表明在指(趾)顶端的浓缩体中表达的Ihh可能调控了指(趾)的形成。这些结果表明Ihh信号减弱是造成中间指(趾)节缩短或缺失的根本原因。
为了揭示Ihh在指(趾)形成中的作用,我们进一步研究了Ihh蛋白诱导的鸡胚指(趾)发育的变化。Ihh蛋白延长了AER中FGF8的表达,扩展了间叶细胞中Sox9的表达区域。FGF8蛋白虽然可以扩展Sox9的表达,但是对指(趾)形成的诱导作用不同于Ihh蛋白。在指(趾)形成早期导入FGF8蛋白可以诱导出额外的指头,在后期导入则抑制末端指节的生成。同时导入Ihh和FGF8蛋白能诱导出一个大的末端指节。这些结果表明Ihh和FGF8在指(趾)形成中扮演了不同的角色并在促进软骨向外生长方面具有协同作用。另外,Ihh蛋白延缓了AER的衰退,FGF8蛋白则促进了AER衰退,这两者对指间间叶细胞的凋亡都有抑制作用。
肢芽内Sox9的表达并不紧靠FGF信号源。我们分析了Sef基因的表达后发现,FGF信号在较近的距离内诱导Sef的表达,在较远的距离处诱导Sox9的表达。Sef是FGF信号的拮抗剂,有可能抑制了FGF信号诱导Sox9表达的胞内通路。据此,我们提出了一个新的反馈抑制模型。在未来的研究中验证这一模型,能够为揭示如何协调间叶细胞的维持和分化这一骨发育中的关键问题提供重要证据。
In 1903, Farabee reported the first recorded disorder of human autosomal dominant Mendelian trait, a kind of inherited digit malformation. In 1951, Bell classified this disorder as brachydactyly type A1 (BDA1), which is characterized by shortening or missing of the middle phalanges. In 2001, Gao et al reported that heterozygous missense mutations in the Ihh gene caused BDA1. In this project, we analyzed three mutants and explored the molecular mechanism of digit formation.
We studied the activity of Ihh signal by in vitro induction and in vivo induction. In in vitro study, we compared the induction effect of wildtype Ihh with three mutants. When C3H10T1/2 cells were induced by the plasmids which expressed the full length wildtype and mutant Ihh proteins, the mutants showed decreased effect, but didn’t completely lose it. The induction of purified N-Ihh proteins showed similar results. Ihh expression pattern in chicks implicates that Ihh expressed in the tip of the digit plays a role in digit patterning. In in vivo study, Application of wildtype N-Ihh to the interdigital spaces in chick embryos resulted in up-regulated activity of Ihh signal pathway in mesenchyme and elongation of penultimate phalange, even an appearance of extra phalange. These results demonstrated that the reduced Ihh signal was the fundamental cause of BDA1.
To discover the role of Ihh in digit formation, we further studied the changes of digit development induced by N-Ihh. This protein prolonged FGF8 expression in AER and expanded Sox9 expression in mesenchyme. FGF8 protein also expanded Sox9 expression, but its induction effect on digit formation was different from N-Ihh. Application of FGF8 at early stage induced extra digit and at later stage inhibited distal phalange formation. Application of both N-Ihh and FGF8 induced a large distal phalange. These results suggest Ihh and FGF8 play different roles and act synergistically to promote chondrogenesis during digit primordial elongation. Moreover, N-Ihh delayed AER regression and FGF8 accelerated AER regression. Both of them restrained mesenchymal cell apoptosis.
Sox9 expression was not adjacent to the source of FGF signal. After analysis of Sef expression, we found that FGF signal induced Sef expression in the short range and Sox9 expression in the long range. Sef is an antagonist of FGF signal and possibly inhibites the intracellular pathway which activates Sox9 expression. We proposed a new model for negative feedback to explain this phenomenon. Further study on this model will provide important evidence for revealing pivotal mechanisms of bone development in which survival and differentiation of mesenchymal cells are coordinated.
我们从体外诱导和体内诱导两个方面研究了Ihh的信号活性。在体外实验中,我们比较了野生型Ihh和三个突变型Ihh之间诱导效应的差异。用表达全长Ihh的质粒来诱导C3H10T1/2细胞,结果显示突变型Ihh的诱导效应明显减弱,但没有完全丧失。用原核表达并纯化的N-Ihh蛋白诱导C3H10T1/2细胞,结果与质粒诱导相仿。在体内实验中,我们将野生型N-Ihh蛋白导入到鸡胚指间区域,导致间叶细胞内Ihh信号通路活性上升和倒数第二指节变长,甚至长出额外的指节。Ihh在鸡胚中的表达模式分析表明在指(趾)顶端的浓缩体中表达的Ihh可能调控了指(趾)的形成。这些结果表明Ihh信号减弱是造成中间指(趾)节缩短或缺失的根本原因。
为了揭示Ihh在指(趾)形成中的作用,我们进一步研究了Ihh蛋白诱导的鸡胚指(趾)发育的变化。Ihh蛋白延长了AER中FGF8的表达,扩展了间叶细胞中Sox9的表达区域。FGF8蛋白虽然可以扩展Sox9的表达,但是对指(趾)形成的诱导作用不同于Ihh蛋白。在指(趾)形成早期导入FGF8蛋白可以诱导出额外的指头,在后期导入则抑制末端指节的生成。同时导入Ihh和FGF8蛋白能诱导出一个大的末端指节。这些结果表明Ihh和FGF8在指(趾)形成中扮演了不同的角色并在促进软骨向外生长方面具有协同作用。另外,Ihh蛋白延缓了AER的衰退,FGF8蛋白则促进了AER衰退,这两者对指间间叶细胞的凋亡都有抑制作用。
肢芽内Sox9的表达并不紧靠FGF信号源。我们分析了Sef基因的表达后发现,FGF信号在较近的距离内诱导Sef的表达,在较远的距离处诱导Sox9的表达。Sef是FGF信号的拮抗剂,有可能抑制了FGF信号诱导Sox9表达的胞内通路。据此,我们提出了一个新的反馈抑制模型。在未来的研究中验证这一模型,能够为揭示如何协调间叶细胞的维持和分化这一骨发育中的关键问题提供重要证据。
In 1903, Farabee reported the first recorded disorder of human autosomal dominant Mendelian trait, a kind of inherited digit malformation. In 1951, Bell classified this disorder as brachydactyly type A1 (BDA1), which is characterized by shortening or missing of the middle phalanges. In 2001, Gao et al reported that heterozygous missense mutations in the Ihh gene caused BDA1. In this project, we analyzed three mutants and explored the molecular mechanism of digit formation.
We studied the activity of Ihh signal by in vitro induction and in vivo induction. In in vitro study, we compared the induction effect of wildtype Ihh with three mutants. When C3H10T1/2 cells were induced by the plasmids which expressed the full length wildtype and mutant Ihh proteins, the mutants showed decreased effect, but didn’t completely lose it. The induction of purified N-Ihh proteins showed similar results. Ihh expression pattern in chicks implicates that Ihh expressed in the tip of the digit plays a role in digit patterning. In in vivo study, Application of wildtype N-Ihh to the interdigital spaces in chick embryos resulted in up-regulated activity of Ihh signal pathway in mesenchyme and elongation of penultimate phalange, even an appearance of extra phalange. These results demonstrated that the reduced Ihh signal was the fundamental cause of BDA1.
To discover the role of Ihh in digit formation, we further studied the changes of digit development induced by N-Ihh. This protein prolonged FGF8 expression in AER and expanded Sox9 expression in mesenchyme. FGF8 protein also expanded Sox9 expression, but its induction effect on digit formation was different from N-Ihh. Application of FGF8 at early stage induced extra digit and at later stage inhibited distal phalange formation. Application of both N-Ihh and FGF8 induced a large distal phalange. These results suggest Ihh and FGF8 play different roles and act synergistically to promote chondrogenesis during digit primordial elongation. Moreover, N-Ihh delayed AER regression and FGF8 accelerated AER regression. Both of them restrained mesenchymal cell apoptosis.
Sox9 expression was not adjacent to the source of FGF signal. After analysis of Sef expression, we found that FGF signal induced Sef expression in the short range and Sox9 expression in the long range. Sef is an antagonist of FGF signal and possibly inhibites the intracellular pathway which activates Sox9 expression. We proposed a new model for negative feedback to explain this phenomenon. Further study on this model will provide important evidence for revealing pivotal mechanisms of bone development in which survival and differentiation of mesenchymal cells are coordinated.
引文
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