YAP/TAZ and Hedgehog Coordinate Growth and Patterning in Gastrointestinal Mesenchyme

YAP/TAZ are the major mediators of mammalian Hippo signaling; however, their precise function in the gastrointestinal tract remains poorly understood. Here we dissect the distinct roles of YAP/TAZ in endodermal epithelium and mesenchyme and find that, although dispensable for gastrointestinal epithelial development and homeostasis, YAP/TAZ function as the critical molecular switch to coordinate growth and patterning in gut mesenchyme. Our genetic analyses reveal that Lats1/2 kinases suppress expansion of the primitive mesenchymal progenitors, where YAP activation also prevents induction of the smooth muscle lineage through transcriptional repression of Myocardin. During later development, zone-restricted downregulation of YAP/TAZ provides the positional cue and allows smooth muscle cell differentiation induced by Hedgehog signaling. Taken together, our studies identify the mesenchymal requirement of YAP/TAZ in the gastrointestinal tract and highlight the functional interplays between Hippo and Hedgehog signaling underlying temporal and spatial control of tissue growth and specification in developing gut. The precise function of the Hippo effectors, YAP/TAZ, in the gastrointestinal tract remains elusive. Cotton et al. identify a key role of YAP/TAZ in coordination of growth and patterning in gut mesenchyme and highlight the functional interplay between Hippo and Hedgehog signaling underlying the spatial-temporal control of smooth muscle specification.