<i>Pitx2</i> patterns an accelerator-brake mechanical feedback through latent TGFβ to rotate the gut.

Abstract

The vertebrate intestine forms by asymmetric gut rotation and elongation, and errors cause lethal obstructions in human infants. Rotation begins with tissue deformation of the dorsal mesentery, which is dependent on left-sided expression of the Paired-like transcription factor <i>Pitx2</i>. The conserved morphogen <i>Nodal</i> induces asymmetric <i>Pitx2</i> to govern embryonic laterality, but organ-level regulation of <i>Pitx2</i> during gut asymmetry remains unknown. We found <i>Nodal</i> to be dispensable for <i>Pitx2</i> expression during mesentery deformation. Intestinal rotation instead required a mechanosensitive latent transforming growth factor-β (TGFβ), tuning a second wave of <i>Pitx2</i> that induced reciprocal tissue stiffness in the left mesentery as mechanical feedback with the right side. This signaling regulator, an accelerator (right) and brake (left), combines biochemical and biomechanical inputs to break gut morphological symmetry and direct intestinal rotation.