The novel transmembrane protein Tmem2 is essential for coordination of myocardial and endocardial morphogenesis

Abstract

SUMMARYCoordination 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.

Tmem88a mediates GATA-dependent specification of cardiomyocyte progenitors by restricting WNT signaling

“…Our findings suggest that Tmem88a is much less effective at WNT repression than Dkk1, a soluble WNT inhibitor. The effect of Tmem2 on BMP activation also seems moderate (Smith et al, 2011;Totong et al, 2011). TMEM proteins might therefore constitute a novel regulatory layer that is responsible for the fine-tuning of major signaling cascades in cardiogenesis.…”

“…Recent forward genetic screens identified Tmem2 as a protein involved in cardiomyocyte migration and atrioventricular canal formation (Smith et al, 2011;Totong et al, 2011). Tmem2 was shown to act by negatively modulating BMP signaling.…”

Development of the larval lymphatic system in the zebrafish

“…The DNA construct was microinjected into the blastomere of one-cell stage zebrafish embryos. Tg (lyve1:dsRed) nz101 , Tg( prox1aBAC:KalTA4-4xUAS-E1b:uncTagRFP) nim5 , Tg(gata1:dsRed) sd2 , Tg(lck:GFP), Tg(mpx:GFP) i114 , Tg(fliep:gal4ff ) ubs4 , Tg(UAS:Kaede) and TgBAC( pdgfrb:mCitrine) were obtained from previous studies (Hatta et al, 2006;Langenau et al, 2004;Okuda et al, 2012;Renshaw et al, 2006;Totong et al, 2011;Traver et al, 2003;van Impel et al, 2014;Vanhollebeke et al, 2015). For the experiments performed using larvae older than 7 dpf, transgenics were crossed to casper (nacre −/− , roy −/− ) background to avoid pigmentation (White et al, 2008).…”

The force within: endocardial development, mechanotransduction and signalling during cardiac morphogenesis

“…One candidate that mediates this is Transmembrane protein 2 (Tmem2), a single-pass transmembrane protein conserved in vertebrates that is expressed in both the myocardium and endocardium (Smith et al, 2011;Totong et al, 2011). tmem2 mRNA is contributed maternally and is required for the midline migration of cardiac progenitors; the correct fusion of myocardial and endocardial cell populations does not occur in maternal-zygotic tmem2 mutants .…”