LIM homeobox transcription factors integrate signaling events that control three-dimensional limb patterning and growth
LIM homeobox transcription factors integrate signaling events that control three-dimensional limb patterning and growth
复制标题
DOI：
10.1242/dev.026476
复制
发表时间：
2009-04-15
期刊：
影响因子：
4.6
通讯作者：
Yang, Yingzi
中科院分区：
文献类型：
--
作者：
Tzchori, Itai;Day, Timothy F.;Yang, Yingzi
脊椎动物肢体的发育由三个信号中心控制，它们分别调节近端(PD)、前后部(AP)和背腹部(DV)肢轴上的肢体模式和生长。肢体沿这三个轴的协调发展是通过相互作用和反馈环实现的，这些相互作用和反馈环涉及到调节这些信号中心活动的分泌信号分子。然而，目前尚不清楚这些信号相互作用是如何在反应细胞中进行处理的。我们发现，由LIM Homeobox(LIM-HD)基因LHX2、Lhx9和Lmx1b编码的不同的LIM同源结构域转录因子整合了连接肢体模式和沿所有三个轴生长的信号事件。LHX2和Lhx9功能的同时丧失导致了AP和PD肢体轴线的图案化和生长缺陷。当三个因子Lmx1b、Lhx2和Lhx9的活性都显著降低时，观察到了类似的、但更严重的表型。提示背侧肢体特异性因子Lmx1b可以部分补偿LHX2和Lhx9在调节AP和PD肢体构型和突起中的作用。我们进一步证明了LHX2和Lhx9在控制间充质细胞对Fgf8和Shh信号反应的输出信号的产生方面可以完全相互替代，Lmx1b是部分冗余的。我们的结果表明，几个不同的LIM-HD转录因子与它们的LDB1辅助因子一起，作为不同信号相互作用和反馈环的共同中央整合因子，在肢芽形成后协调肢体图案和沿PD、AP和DV轴的生长。
Vertebrate limb development is controlled by three signaling centers that regulate limb patterning and growth along the proximodistal (PD), anteroposterior (AP) and dorsoventral (DV) limb axes. Coordination of limb development along these three axes is achieved by interactions and feedback loops involving the secreted signaling molecules that mediate the activities of these signaling centers. However, it is unknown how these signaling interactions are processed in the responding cells. We have found that distinct LIM homeodomain transcription factors, encoded by the LIM homeobox (LIM-HD) genes Lhx2, Lhx9 and Lmx1b integrate the signaling events that link limb patterning and outgrowth along all three axes. Simultaneous loss of Lhx2 and Lhx9 function resulted in patterning and growth defects along the AP and the PD limb axes. Similar, but more severe, phenotypes were observed when the activities of all three factors, Lmx1b, Lhx2 and Lhx9, were significantly reduced by removing their obligatory cofactor Ldb1. This reveals that the dorsal limb-specific factor Lmx1b can partially compensate for the function of Lhx2 and Lhx9 in regulating AP and PD limb patterning and outgrowth. We further showed that Lhx2 and Lhx9 can fully substitute for each other, and that Lmx1b is partially redundant, in controlling the production of output signals in mesenchymal cells in response to Fgf8 and Shh signaling. Our results indicate that several distinct LIM-HD transcription factors in conjunction with their Ldb1 co-factor serve as common central integrators of distinct signaling interactions and feedback loops to coordinate limb patterning and outgrowth along the PD, AP and DV axes after limb bud formation.