Liu Jiandong, Qian Li, Wessells Robert J, Bidet Yannick, Jagla Krzysztof, Bodmer Rolf
The Burnham Institute, Center for Neurosciences and Aging, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Dev Biol. 2006 Feb 15;290(2):373-85. doi: 10.1016/j.ydbio.2005.11.033. Epub 2006 Jan 4.
The Drosophila heart is a highly ordered structure with only a limited number of cell types, which are arranged in a stereotyped metameric pattern. Ras signaling has previously been implicated in contributing to heart formation, but how positional information is integrated with this pathway to specify, distinguish and precisely position individual cardiac progenitors within the presumptive heart-forming region are not known. Here, we present evidence that the striped pattern of the secreted factor Hedgehog (Hh), in combination with the RAS pathway, specifies and positions neighboring groups of cardiac progenitors within each segment: the anterior ladybird (lbe)- and the posterior even skipped (eve)-expressing cardiac progenitors. Loss of hh function (while maintaining wg activity) results in the absence of the Eve cells, whereas the Lbe cells are expanded within the cardiac mesoderm. Overexpressing the repressor form of Cubitus interruptus (Ci), a Hh pathway antagonist, also results in expansion of Lbe at the expense of Eve, as does lowering Ras signaling. Conversely, overexpression of Hh or increasing Ras signaling eliminates Lbe expression while expanding Eve within the cardiogenic mesoderm. Increasing Ras signaling in the absence of Hh suggests that the Ras pathway is in part epistatic to Hh. Hh controls dorsal mesodermal Ras signaling by transcriptional regulation of the EGF receptor ligand protease, encoded by rhomboid (rho). Conversely, Hh overexpression can fully inhibit Lbe even when Ras signaling is much reduced, suggesting that Hh also acts in parallel to Ras. We propose that the Eve precursors next to the Hh stripe are distinguished from more distant Lbe precursors by locally augmenting Ras signaling via elevating rho transcripts. Thus, the spatial precision of cell type specification within an organ depends on multiple phases of inductive interaction between the ectoderm and the mesoderm.
果蝇的心脏是一种高度有序的结构，只有有限数量的细胞类型，它们以一种刻板的体节模式排列。Ras信号通路先前被认为与心脏形成有关，但位置信息如何与该通路整合，以在假定的心脏形成区域内指定、区分并精确定位单个心脏祖细胞尚不清楚。在这里，我们提供证据表明，分泌因子Hedgehog（Hh）的条纹模式与RAS通路相结合，在每个节段内指定并定位相邻的心脏祖细胞群：即表达前瓢虫（lbe）和后偶数跳动（eve）的心脏祖细胞。hh功能丧失（同时维持wg活性）会导致Eve细胞缺失，而Lbe细胞在心脏中胚层内扩张。过表达Hh通路拮抗剂Cubitus interruptus（Ci）的阻遏形式，也会导致Lbe以Eve为代价扩张，降低Ras信号通路也是如此。相反，过表达Hh或增加Ras信号通路会消除Lbe表达，同时在心脏中胚层内扩张Eve。在没有Hh的情况下增加Ras信号通路表明，Ras通路部分上位到Hh。Hh通过对由菱形（rho）编码 的表皮生长因子受体配体蛋白酶进行转录调控来控制背侧中胚层Ras信号通路。相反，即使Ras信号通路大大降低，Hh过表达也能完全抑制Lbe，这表明Hh也与Ras平行发挥作用。我们提出，靠近Hh条纹的Eve前体通过升高rho转录本局部增强Ras信号通路，与更远的Lbe前体区分开来。因此，器官内细胞类型指定的空间精度取决于外胚层和中胚层之间诱导相互作用的多个阶段。
