Multiplexin promotes heart but not aorta morphogenesis by polarized enhancement of slit/robo activity at the heart lumen.
Multiplexin promotes heart but not aorta morphogenesis by polarized enhancement of slit/robo activity at the heart lumen.
复制标题
DOI：
10.1371/journal.pgen.1003597
复制
发表时间：
2013-06
期刊：
影响因子：
4.5
通讯作者：
Volk T
中科院分区：
文献类型：
--
作者：
Harpaz N;Ordan E;Ocorr K;Bodmer R;Volk T
果蝇的心管结构与脊椎动物的初级心管相似，具有较大的管腔；在果蝇和脊椎动物中促进心管形态的机制尚不清楚。我们确定了多重蛋白（multiexin, Mp），这是哺乳动物胶原蛋白xv /XVIII的果蝇同源物，也是迄今为止在果蝇中描述的唯一的心脏特异性结构蛋白，对于心脏管腔的形成是必要的和充分的，但对主动脉却不是。Mp在心管闭合阶段特异性表达，以极化方式，独特地沿着成心细胞管腔膜表达，其缺失导致心管管腔非常小。重要的是，Mp与Slit形成一种蛋白质复合物，并在心脏管的形成过程中与Slit和robo基因相互作用。Mp在成心细胞中的过度表达以狭缝依赖的方式促进大的心腔。此外，Mp改变了Slit的分布，促进了多个Slit内吞囊泡的形成，类似于在这些细胞中过表达Robo的作用。我们的数据与mp依赖性的Slit/Robo活性和信号的增强是一致的，可能是通过影响Slit蛋白的稳定性，特别是在心脏管的管腔侧。这种活性导致心脏管腔膜上f -肌动蛋白水平的局部减少，这是形成大心脏管腔所必需的。因此，Mp缺乏导致舒张能力下降，导致心脏收缩力降低，如在活蝇心脏中测量的那样。综上所述，这些发现表明Mp的极化定位控制着成心细胞腔膜上Slit/Robo活性和信号传导的方向、时间以及可能的程度。这种调节对果蝇心脏管的形态发生变化至关重要，也可能对脊椎动物初级心脏管的形成至关重要。特征性的大心腔的形成是所有含心生物共同的，对有效的心脏功能至关重要；然而，促进这一过程的结构成分尚未阐明。果蝇的心脏代表了一个特殊的隔室，它位于一个细长的可收缩管（背侧血管）内，对将血淋巴输送到整个果蝇身体至关重要。在这里，我们描述了一种新的细胞外基质成分，multiexin (Mp)，与脊椎动物胶原蛋白XV/XVIII同源，它是促进大心脏腔的必要和充分的。基于分子和遗传分析，我们的发现将Mp活性与先前证明的抑制迁移神经元前沿肌动蛋白聚合的信号通路（Slit/Robo）联系起来。我们一致地表明，Mp沉积在管腔膜上增强了Slit/Robo活性和可能的信号传导，导致肌动蛋白水平降低，这是管腔膜弯曲和大心脏管腔形成所必需的。因此，mp突变果蝇表现出狭窄的心脏和降低的心脏收缩力。这些结果证明了一种新的机制，通过这种机制，ECM成分的局部沉积促进了一对成心细胞腔内的极化信号，形成了大的心管腔室。
The Drosophila heart tube represents a structure that similarly to vertebrates' primary heart tube exhibits a large lumen; the mechanisms promoting heart tube morphology in both Drosophila and vertebrates are poorly understood. We identified Multiplexin (Mp), the Drosophila orthologue of mammalian Collagen-XV/XVIII, and the only structural heart-specific protein described so far in Drosophila, as necessary and sufficient for shaping the heart tube lumen, but not that of the aorta. Mp is expressed specifically at the stage of heart tube closure, in a polarized fashion, uniquely along the cardioblasts luminal membrane, and its absence results in an extremely small heart tube lumen. Importantly, Mp forms a protein complex with Slit, and interacts genetically with both slit and robo in the formation of the heart tube. Overexpression of Mp in cardioblasts promotes a large heart lumen in a Slit-dependent manner. Moreover, Mp alters Slit distribution, and promotes the formation of multiple Slit endocytic vesicles, similarly to the effect of overexpression of Robo in these cells. Our data are consistent with Mp-dependent enhancement of Slit/Robo activity and signaling, presumably by affecting Slit protein stabilization, specifically at the lumen side of the heart tube. This activity results with a Slit-dependent, local reduction of F-actin levels at the heart luminal membrane, necessary for forming the large heart tube lumen. Consequently, lack of Mp results in decreased diastolic capacity, leading to reduced heart contractility, as measured in live fly hearts. In summary, these findings show that the polarized localization of Mp controls the direction, timing, and presumably the extent of Slit/Robo activity and signaling at the luminal membrane of the heart cardioblasts. This regulation is essential for the morphogenetic changes that sculpt the heart tube in Drosophila, and possibly in forming the vertebrates primary heart tube. The formation of the characteristic large heart lumen is common to all heart-containing organisms and is essential for efficient heart function; however, the structural components promoting this process are yet to be elucidated. The Drosophila heart represents a specific compartment within an elongated contractile tube, the dorsal vessel, essential for pumping the hemolymph throughout the fly body. Here, we describe a novel extracellular matrix component, Multiplexin (Mp), homologous to vertebrates Collagen XV/XVIII, which is necessary and sufficient for promoting the large heart lumen. Based on molecular and genetic analysis, our findings link Mp activity to a signaling pathway (Slit/Robo) demonstrated previously to repress actin polymerization at the leading edge of migrating neurons. Consistently we show that Mp deposited at the luminal membrane enhances Slit/Robo activity and presumably signaling, leading to reduced actin levels, necessary for curving of the luminal membrane, and for the formation of the large heart lumen. Consequently, mp mutant flies exhibit narrow heart and reduced heart contractility. These results demonstrate a novel mechanism by which local deposition of an ECM component promotes a polarized signaling at the luminal aspects of a pair of cardioblasts, shaping the large heart tube compartment.
登录
查看更多内容
影响因子：
4.6
作者：
Gilsohn, Eliezer;Volk, Talila
通讯作者：
Volk, Talila
DOI：
10.1083/jcb.200203064
发表时间：
2002-08-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hanai J;Gloy J;Karumanchi SA;Kale S;Tang J;Hu G;Chan B;Ramchandran R;Jha V;Sukhatme VP;Sokol S
通讯作者：
Sokol S
DOI：
10.1073/pnas.0901148106
发表时间：
2009-07-21
影响因子：
11.1
作者：
Chanana, Bhavna;Steigemann, Patrick;Vorbrueggen, Gerd
通讯作者：
Vorbrueggen, Gerd
DOI：
10.1073/pnas.0609278104
发表时间：
2007-03-06
影响因子：
11.1
作者：
Ocorr, Karen;Reeves, Nick L.;Bodmer, Rolf
通讯作者：
Bodmer, Rolf
DOI：
10.1590/s0001-37652006000100012
发表时间：
2006-03-01
期刊：
Anais da Academia Brasileira de Ciências
影响因子：
--
作者：
Passos-Bueno, Maria Rita;Suzuki, Oscar T.;Leite, Katia R.M.
通讯作者：
Leite, Katia R.M.