Heterotrimeric G Proteins Regulate a Noncanonical Function of Septate Junction Proteins to Maintain Cardiac Integrity in Drosophila

The gene networks regulating heart morphology and cardiac integrity are largely unknown. We previously reported a role for the heterotrimeric G protein gamma subunit 1 (G gamma 1) in mediating cardial-pericardial cell adhesion in Drosophila. Here we show G-o alpha 47A and G beta 13F cooperate with G gamma 1 to maintain cardiac integrity. Cardial-pericardial cell adhesion also relies on the septate junction (SJ) proteins Neurexin-IV (Nrx-IV), Sinuous, Coracle, and Nervana2, which together function in a common pathway with G gamma 1. Furthermore, G gamma 1 signaling is required for proper SJ protein localization, and loss of at least one SJ protein, Nrx-IV, induces cardiac lumen collapse. These results are surprising because the embryonic heart lacks SJs and suggest that SJ proteins perform non-canonical functions to maintain cardiac integrity in Drosophila. Our findings unveil the components of a previously unrecognized network of genes that couple G protein signaling with structural constituents of the heart.