Development of the Proximal-Anterior Skeletal Elements in the Mouse Hindlimb Is Regulated by a Transcriptional and Signaling Network Controlled by Sall4
Development of the Proximal-Anterior Skeletal Elements in the Mouse Hindlimb Is Regulated by a Transcriptional and Signaling Network Controlled by Sall4
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DOI：
10.1534/genetics.120.303069
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发表时间：
2020-05-01
期刊：
影响因子：
3.3
通讯作者：
Kawakami, Yasuhiko
中科院分区：
文献类型：
--
作者：
Chen, Katherine Q.;Tahara, Naoyuki;Kawakami, Yasuhiko
脊椎动物肢体作为研究调节典型骨骼元素发育机制的实验范例。在这项研究中，我们在小鼠胚胎中同时使用 Hoxb6Cre 和 Plzf 灭活 Sall4，发现它们的联合功能调节后肢近端前部骨骼元件的发育。萨尔4； Plzf 双敲除在股骨、胫骨和前指中表现出严重缺陷，与 Sall4 的其他等位基因系列相比，这是明显的缺陷；请。我们发现 Sall4 在后肢生长之前调节 Plzf 表达。进一步的表达分析表明Hox10基因和GLI3在Sall4中严重下调； Plzf 双敲除后肢芽。相反，PLZF 表达减少，但在 Sall4 中可检测到； Gli3双敲除肢芽，SALL4在Plzf中表达； Gli3 双敲除肢芽。这些结果表明 Sall4 下游的 Plzf、Gli3 和 Hox10 基因调节股骨和胫骨的发育。在 autopod 中，我们发现 Sall4 负向调节 Hedgehog 信号，从而允许最前面的手指发育。总的来说，我们的研究阐明了调节后肢近端前部骨骼元件发育的遗传系统。
The vertebrate limb serves as an experimental paradigm to study mechanisms that regulate development of the stereotypical skeletal elements. In this study, we simultaneously inactivated Sall4 using Hoxb6Cre and Plzf in mouse embryos, and found that their combined function regulates development of the proximal-anterior skeletal elements in hindlimbs. The Sall4; Plzf double knockout exhibits severe defects in the femur, tibia, and anterior digits, distinct defects compared to other allelic series of Sall4; Plzf. We found that Sall4 regulates Plzf expression prior to hindlimb outgrowth. Further expression analysis indicated that Hox10 genes and GLI3 are severely downregulated in the Sall4; Plzf double knockout hindlimb bud. In contrast, PLZF expression is reduced but detectable in Sall4; Gli3 double knockout limb buds, and SALL4 is expressed in the Plzf; Gli3 double knockout limb buds. These results indicate that Plzf, Gli3, and Hox10 genes downstream of Sall4, regulate femur and tibia development. In the autopod, we show that Sall4 negatively regulates Hedgehog signaling, which allows for development of the most anterior digit. Collectively, our study illustrates genetic systems that regulate development of the proximal-anterior skeletal elements in hindlimbs.