REGULATION OF HEART ASYMMETRY

Harvard University (Medical School), Boston MA

Investigators

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Abstract

DESCRIPTION (appended verbatim from investigator's abstract): The primitive heart tube forms along the midline and subsequently rotates towards the right, initiating heart morphogenesis. In rare cases, reverse bending (dextrocardia) occurs, associated with a very high incidence of congenital heart disease. The asymmetry of the heart is the first morphological manifestation of left‑right (LR) asymmetry during embryogenesis. Our laboratory and others have recently described a cascade of signals which establish the distinct morphological fate of the left and right sides of the embryo. This ongoing project is focused on understanding the details of this pathway: the activity of cilia at the Node has been correlated with establishment of LR asymmetry in the mouse. We will examine the universality of this mechanism and attempt to obtain experimental evidence in favor of the hypothesis in the chick. The subsequent transfer of LR information is mediated through a complex signaling cascade. The secreted proteins Wnt8c and Fhf2 are asymmetrically expressed during gastrulation. The roles of these signals in LR patterning will be defined. At later stages, the LR signaling is propagated by the BMP antagonist Caronte. The LR‑specific factors need to be restricted to a simple side and this is accomplished, in part, by the activity of the BMP‑related protein Lefty. We will test whether Caronte protein directly interacts with Lefty. Finally, the end point of the signaling cascade is to direct asymmetric morphogenesis. As a step towards understanding how this occurs, we will screen for targets of LR signaling using a B‑lactamase reporter/gene trap strategy.