Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.
iCAN Digital Precision Cancer Medicine Flagship, Research Programs Unit, Faculty of Medicine and HiLIFE-Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.
Nat Commun. 2021 Dec 10;12(1):7186. doi: 10.1038/s41467-021-27319-z.
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.
管状器官如何伸长的机制尚不清楚。我们发现，肠道壁中减弱的纤毛 Hedgehog 信号会损害环形平滑肌的模式形成，并抑制正在发育的肠道和食管的增殖和伸长。同样，肠壁平滑肌细胞的消融会减少伸长。纤毛 Hedgehog 信号的破坏或平滑肌的去除会降低肠道壁内的残余应力，并降低机械转导效应物 Yap 的活性。间质中 Yap 的去除也会减少增殖和伸长，但不会影响平滑肌的形成，这表明 Yap 解释平滑肌产生的力以促进纵向生长。此外，我们开发了一种肠道培养系统，该系统再现了纤毛和机械力在伸长中的要求。在该系统中，通过药理学激活 Yap 可恢复纤毛缺陷肠的伸长。因此，我们的结果表明，纤毛 Hedgehog 信号会对环形平滑肌进行模式化，以产生径向机械力，从而激活 yap 并使肠道伸长。
