Haemodynamically dependent valvulogenesisof zebrafish heart is mediated by flow-dependentexpression of miR-21

摘要

Heartbeat is required for normal development of the heart, and perturbation of intracardiacflow leads to morphological defects resembling congenital heart diseases. These observationsimplicate intracardiac haemodynamics in cardiogenesis, but the signalling cascadesconnecting physical forces, gene expression and morphogenesis are largely unknown. Herewe use a zebrafish model to show that the microRNA, miR-21, is crucial for regulation of heartvalve formation. Expression of miR-21 is rapidly switched on and off by blood flow.Vasoconstriction and increasing shear stress induce ectopic expression of miR-21 in the headvasculature and heart. Flow-dependent expression of mir-21 governs valvulogenesis byregulating the expression of the same targets as mouse/human miR-21 (sprouty, pdcd4, ptenb)and induces cell proliferation in the valve-forming endocardium at constrictions in the hearttube where shear stress is highest. We conclude that miR-21 is a central component of aflow-controlled mechanotransduction system in a physicogenetic regulatory loop.