RESUMO
During heart development, the onset of heartbeat and blood flow coincides with a ballooning of the cardiac chambers. Here, we have used the zebrafish as a vertebrate model to characterize chamber ballooning morphogenesis of the endocardium, a specialized population of endothelial cells that line the interior of the heart. By combining functional manipulations, fate mapping studies, and high-resolution imaging, we show that endocardial growth occurs without an influx of external cells. Instead, endocardial cell proliferation is regulated, both by blood flow and by Bmp signaling, in a manner independent of vascular endothelial growth factor (VEGF) signaling. Similar to myocardial cells, endocardial cells obtain distinct chamber-specific and inner- versus outer-curvature-specific surface area sizes. We find that the hemodynamic-sensitive transcription factor Klf2a is involved in regulating endocardial cell morphology. These findings establish the endocardium as the flow-sensitive tissue in the heart with a key role in adapting chamber growth in response to the mechanical stimulus of blood flow.
Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Endocárdio/embriologia , Hemodinâmica , Fatores de Transcrição Kruppel-Like/metabolismo , Morfogênese , Proteínas de Peixe-Zebra/metabolismo , Animais , Movimento Celular , Proliferação de Células , Endocárdio/citologia , Endocárdio/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/fisiologia , Fatores de Transcrição Kruppel-Like/genética , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Peixe-Zebra , Proteínas de Peixe-Zebra/genéticaRESUMO
Signaling by Nodal and Bmp is essential for cardiac laterality. How activities of these pathways translate into left-right asymmetric organ morphogenesis is largely unknown. We show that, in zebrafish, Nodal locally reduces Bmp activity on the left side of the cardiac field. This effect is mediated by the extracellular matrix enzyme Hyaluronan synthase 2, expression of which is induced by Nodal. Unilateral reduction of Bmp signaling results in lower expression of nonmuscle myosin II and higher cell motility on the left, driving asymmetric displacement of the entire cardiac field. In silico modeling shows that left-right differences in cell motility are sufficient to induce a robust, directional migration of cardiac tissue. Thus, the mechanism underlying the formation of cardiac left-right asymmetry involves Nodal modulating an antimotogenic Bmp activity.