Pax9 and Jagged1 act downstream of Gli3 in vertebrate limb development
Pax9 and Jagged1 act downstream of Gli3 in vertebrate limb development
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DOI：
10.1016/j.mod.2005.06.012
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发表时间：
2005-11-01
影响因子：
2.6
通讯作者：
Wicking, C
中科院分区：
文献类型：
--
作者：
McGlinn, E;van Bueren, KL;Wicking, C
从肢体发育的早期开始，转录因子Gli3就沿着前后(AP)轴定义基因表达的边界，建立提供位置信息所需的不对称模式。随着肢体发育的进行，Sonic hedgehog(Shh)的后部间充质表达调节Gli3的转录和翻译后处理，以确定数字和身份。在肢体发育的后期阶段，依赖于Gli3的分子级联将早期的图案化事件与最终的手指形态发生联系在一起，仍然缺乏特征。通过分析多指突变小鼠外脚趾(Gli3(XT/XT))E11.5和E12.5肢芽前缘Gli3缺失的转录后果，我们已经确定了一些依赖于肢体Gli3的已知和新的转录本。特别是，我们证明了编码成对的盒转录因子Pax9、Notch配体Jagged1和细胞表面受体CDO的基因依赖于Gli3在前肢间充质中正确表达。分析Shh；Gli3复合突变小鼠胚胎中的表达，以及体外和体内Shh信号分析，进一步明确Shh调控Gli3的加工在控制基因表达中的重要性。特别是，Shh和Gli3对Pax9的调节被证明是上下文相关的，Shh珠在雏鸡体内的植入实验揭示了肢体和体节之间的主要差异。Shh在雏鸡肢体和C3H10T1/2细胞的信号传递实验中显示Jagged1被诱导，Shh；Gli3突变分析表明Jagged1的表达依赖于Gli3的去抑制。我们的数据还显示，Gli3(XT/XT)肢体内早期模式事件的扰动最终导致前软骨形成的特定延迟，这随后被实现为额外的数字。(C)2005爱思唯尔爱尔兰有限公司。保留所有权利。
From early in limb development the transcription factor Gli3 acts to define boundaries of gene expression along the anterior-posterior (AP) axis, establishing asymmetric patterns required to provide positional information. As limb development proceeds, posterior mesenchyme expression of Sonic hedgehog (Shh) regulates Gli3 transcription and post-translational processing to specify digit number and identity. The molecular cascades dependent on Gli3 at later stages of limb development, which link early patterning events with final digit morphogenesis, remain poorly characterised. By analysing the transcriptional consequences of loss of Gli3 in the anterior margin of the E11.5 and E12.5 limb bud in the polydactylous mouse mutant extra-toes (Gli3(Xt/Xt)), we have identified a number of known and novel transcripts dependent on Gli3 in the limb. In particular, we demonstrated that the genes encoding the paired box transcription factor Pax9, the Notch ligand Jagged1 and the cell surface receptor Cdo are dependent on Gli3 for correct expression in the anterior limb mesenchyme. Analysis of expression in compound Shh;Gli3 mutant mouse embryos and in both in vitro and in vivo Shh signaling assays, further defined the importance of Shh regulated processing of Gli3 in controlling gene expression. In particular Pax9 regulation by Shh and Gli3 was shown to be context dependent, with major differences between the limb and somite revealed by Shh bead implantation experiments in the chick. Jagged1 was shown to be induced by Shh in the chick limb and in a C3H10T1/2 cell based signaling assay, with Shh;Gli3 mutant analysis indicating that expression is dependent on Gli3 derepression. Our data have also revealed that perturbation of early patterning events within the Gli3(Xt/Xt), limb culminates in a specific delay of anterior chondrogenesis which is subsequently realised as extra digits. (c) 2005 Elsevier Ireland Ltd. All rights reserved.