Qian Li, Liu Jiandong, Bodmer Rolf
The Burnham Institute, Center for Neuroscienes and Aging, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.
Curr Biol. 2005 Dec 20;15(24):2271-8. doi: 10.1016/j.cub.2005.10.037.
Basic aspects of heart morphogenesis involving migration, cell polarization, tissue alignment, and lumen formation may be conserved between Drosophila and humans, but little is known about the mechanisms that orchestrate the assembly of the heart tube in either organism. The extracellular-matrix molecule Slit and its Robo-family receptors are conserved regulators of axonal guidance. Here, we report a novel role of the Drosophila slit, robo, and robo2 genes in heart morphogenesis. Slit and Robo proteins specifically accumulate at the dorsal midline between the bilateral myocardial progenitors forming a linear tube. Manipulation of Slit localization or its overexpression causes disruption in heart tube alignment and assembly, and slit-deficient hearts show disruptions in cell-polarity marker localization within the myocardium. Similar phenotypes are observed when Robo and Robo2 are manipulated. Rescue experiments suggest that Slit is secreted from the myocardial progenitors and that Robo and Robo2 act in myocardial and pericardial cells, respectively. Genetic interactions suggest a cardiac morphogenesis network involving Slit/Robo, cell-polarity proteins, and other membrane-associated proteins. We conclude that Slit and Robo proteins contribute significantly to Drosophila heart morphogenesis by guiding heart cell alignment and adhesion and/or by inhibiting cell mixing between the bilateral compartments of heart cell progenitors and ensuring proper polarity of the myocardial epithelium.
果蝇和人类在心脏形态发生的基本方面可能存在保守性，这些方面包括迁移、细胞极化、组织排列和管腔形成，但对于在任一生物体中协调心脏管组装的机制却知之甚少。细胞外基质分子Slit及其Robo家族受体是轴突导向的保守调节因子。在此，我们报道了果蝇slit、robo和robo2基因在心脏形态发生中的新作用。Slit和Robo蛋白特异性地聚集在形成线性管的双侧心肌祖细胞之间的背中线处。操纵Slit的定位或其过表达会导致心脏管排列和组装的破坏，并且缺乏slit的心脏在心肌内的细胞极性标记定位方面表现出破坏。当操纵Robo和Robo2时，观察到类似的表型。拯救实验表明，Slit由心肌祖细胞分泌，并且Robo和Robo2分别在心肌细胞和心包细胞中起作用。遗传相互作用提示了一个涉及Slit/Robo、细胞极性蛋白和其他膜相关蛋白的心脏形态发生网络。我们得出结论，Slit和Robo蛋白通过引导心脏细胞排列和黏附，和/或通过抑制心脏细胞祖细胞双侧区室之间的细胞混合并确保心肌上皮的正确极性，对果蝇心脏形态发生做出了重大贡献。
