Abstract
How tubular organs elongate is poorly understood. We found that attenuated ciliary Hedgehog signaling in the gut wall impaired patterning of the circumferential smooth muscle and inhibited proliferation and elongation of developing intestine and esophagus. Similarly, ablation of gut-wall smooth muscle cells reduced lengthening. Disruption of ciliary Hedgehog signaling or removal of smooth muscle reduced residual stress within the gut wall and decreased activity of the mechanotransductive effector YAP. Removing YAP in the mesenchyme also reduced proliferation and elongation, but without affecting smooth muscle formation, suggesting that YAP interprets the smooth muscle-generated force to promote longitudinal growth. Additionally, we developed an intestinal culture system that recapitulates the requirements for cilia and mechanical forces in elongation. Pharmacologically activating YAP in this system restored elongation of cilia-deficient intestines. Thus, our results reveal that ciliary Hedgehog signaling patterns the circumferential smooth muscle to generate radial mechanical forces that activate YAP and elongate the gut.
Highlights
How tubular organs elongate is poorly understood
We investigated the B9 domain-containing 1 (B9d1), Inositol polyphosphate 5-phosphatase (Inpp5e), and Tctn[3] mouse mutants because the homozygous null mutants survive to gestational ages at which intestinal length can be ascertained and because they encode proteins that participate in ciliary signaling through distinct mechanisms
Our results reveal a mechanism of tubular organ elongation by which intercellular signaling events create mechanical forces that are translated into longitudinal growth
Summary
We found that attenuated ciliary Hedgehog signaling in the gut wall impaired patterning of the circumferential smooth muscle and inhibited proliferation and elongation of developing intestine and esophagus. Disruption of ciliary Hedgehog signaling or removal of smooth muscle reduced residual stress within the gut wall and decreased activity of the mechanotransductive effector YAP. Our results reveal that ciliary Hedgehog signaling patterns the circumferential smooth muscle to generate radial mechanical forces that activate YAP and elongate the gut. During E12-13, these smooth muscle cells organize into a distinct circumferential layer[5] The formation of this smooth muscle layer requires Hedgehog (HH) signaling[3,6,7,8,9]. Cilia transduce HH signals to pattern the limb and neural tube[21,22,23,24], whether cilia function in gut development has been unexplored
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