Abstract
During cardiac trabeculation, cardiomyocytes delaminate from the outermost (compact) layer to form complex muscular structures known as trabeculae. As these cardiomyocytes delaminate, the remodeling of adhesion junctions must be tightly coordinated so cells can extrude from the compact layer while remaining in tight contact with their neighbors. In this study, we examined the distribution of N-cadherin (Cdh2) during cardiac trabeculation in zebrafish. By analyzing the localization of a Cdh2-EGFP fusion protein expressed under the control of the zebrafish cdh2 promoter, we initially observed Cdh2-EGFP expression along the lateral sides of embryonic cardiomyocytes, in an evenly distributed pattern, and with the occasional appearance of punctae. Within a few hours, Cdh2-EGFP distribution on the lateral sides of cardiomyocytes evolves into a clear punctate pattern as Cdh2-EGFP molecules outside the punctae cluster to increase the size of these aggregates. In addition, Cdh2-EGFP molecules also appear on the basal side of cardiomyocytes that remain in the compact layer. Delaminating cardiomyocytes accumulate Cdh2-EGFP on the surface facing the basal side of compact layer cardiomyocytes, thereby allowing tight adhesion between these layers. Importantly, we find that blood flow/cardiac contractility is required for the transition from an even distribution of Cdh2-EGFP to the formation of punctae. Furthermore, using time-lapse imaging of beating hearts in conjunction with a Cdh2 tandem fluorescent protein timer transgenic line, we observed that Cdh2-EGFP molecules appear to move from the lateral to the basal side of cardiomyocytes along the cell membrane, and that Erb-b2 receptor tyrosine kinase 2 (Erbb2) function is required for this relocalization.
Highlights
During cardiac trabeculation, cardiomyocytes delaminate from the outermost layer to form complex muscular structures known as trabeculae
We show that blood flow and/or cardiac contractility play an essential role in the distribution of Cdh2, one distinct from the role played by Erb-b2 receptor tyrosine kinase 2 (Erbb2) signaling, a critical regulator of cardiac trabeculation
To investigate the question of cardiomyocyte adhesion during cardiac trabeculation in zebrafish, we focused on Cdh2, a highly
Summary
Cardiomyocytes delaminate from the outermost (compact) layer to form complex muscular structures known as trabeculae. Mechanical tension plays a crucial role in regulating the size of cell–cell junctions, and local tension generated by the actomyosin network may modulate cell–cell junction remodeling [24,25,26] These forces can activate vinculin and stabilize E-cadherin/VE-cadherin-mediated cell–cell adhesion [27,28,29]. Additional studies have shown that cadherin punctae formed by the clustering of E-cadherin along cell–cell boundaries can increase in size during the maturation of cell–cell junctions, and that they are important for cell–cell adhesion and force transmission in vivo [26, 30]. Cdh molecules appear on the basal side of compact layer cardiomyocytes, possibly by moving from the lateral sides along the cell membrane. We show that blood flow and/or cardiac contractility play an essential role in the distribution of Cdh, one distinct from the role played by Erbb signaling, a critical regulator of cardiac trabeculation
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