Developmental Genetics Program and Department of Cell Biology, Kimmel Center for Biology and Medicine, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA.
Development. 2011 Oct;138(19):4199-205. doi: 10.1242/dev.064261.
Coordination between adjacent tissues plays a crucial role during the morphogenesis of developing organs. In the embryonic heart, two tissues - the myocardium and the endocardium - are closely juxtaposed throughout their development. Myocardial and endocardial cells originate in neighboring regions of the lateral mesoderm, migrate medially in a synchronized fashion, collaborate to create concentric layers of the heart tube, and communicate during formation of the atrioventricular canal. Here, we identify a novel transmembrane protein, Tmem2, that has important functions during both myocardial and endocardial morphogenesis. We find that the zebrafish mutation frozen ventricle (frv) causes ectopic atrioventricular canal characteristics in the ventricular myocardium and endocardium, indicating a role of frv in the regional restriction of atrioventricular canal differentiation. Furthermore, in maternal-zygotic frv mutants, both myocardial and endocardial cells fail to move to the midline normally, indicating that frv facilitates cardiac fusion. Positional cloning reveals that the frv locus encodes Tmem2, a predicted type II single-pass transmembrane protein. Homologs of Tmem2 are present in all examined vertebrate genomes, but nothing is known about its molecular or cellular function in any context. By employing transgenes to drive tissue-specific expression of tmem2, we find that Tmem2 can function in the endocardium to repress atrioventricular differentiation within the ventricle. Additionally, Tmem2 can function in the myocardium to promote the medial movement of both myocardial and endocardial cells. Together, our data reveal that Tmem2 is an essential mediator of myocardium-endocardium coordination during cardiac morphogenesis.
相邻组织之间的协调在发育器官的形态发生中起着至关重要的作用。在胚胎心脏中，两个组织 - 心肌和心内膜 - 在整个发育过程中紧密相邻。心肌和心内膜细胞起源于侧中胚层的相邻区域，以同步的方式向内侧迁移，协作形成心管的同心层，并在房室管形成过程中进行交流。在这里，我们鉴定出一种新型的跨膜蛋白 Tmem2，它在心肌和心内膜形态发生中具有重要功能。我们发现，斑马鱼突变体“冻结心室”（frv）在心室心肌和心内膜中引起房室管的异位特征，表明 frv 在房室管分化的区域限制中起作用。此外，在母体 - 合子 frv 突变体中，心肌和心内膜细胞都不能正常向中线移动，表明 frv 促进心脏融合。定位克隆表明，frv 基因座编码 Tmem2，这是一种预测的 II 型单次跨膜蛋白。Tmem2 的同源物存在于所有检查过的脊椎动物基因组中，但在任何情况下都不知道其分子或细胞功能。通过使用转基因驱动 tmem2 的组织特异性表达，我们发现 Tmem2 可以在心内膜中发挥作用，抑制心室中心房的分化。此外，Tmem2 可以在心肌中发挥作用，促进心肌和心内膜细胞的向内侧移动。总之，我们的数据表明 Tmem2 是心脏形态发生中心肌 - 心内膜协调的重要介质。
