Yap controls notochord formation and neural tube patterning by integrating mechanotransduction with <i>FoxA2</i> and <i>Shh</i> expression.

Abstract

Correct notochord and neural tube (NT) formation is crucial to the development of the central nervous system and midline structures. Integrated biochemical and biophysical signaling controls embryonic growth and patterning; however, the underlying mechanisms remain poorly understood. Here, we took the opportunities of marked morphological changes during notochord and NT formation and identified both necessary and sufficient roles of Yap, a key mechanosensor and mechanotransducer, in biochemical signaling activation during formation of notochord and floor plate, the ventral signaling centers that pattern the dorsal-ventral axis of NT and the surrounding tissues. We showed that Yap activation by a gradient of mechanical stress and tissue stiffness in the notochord and ventral NT induces <i>FoxA2</i> and <i>Shh</i> expression. Hedgehog signaling activation rescued NT patterning defects caused by <i>Yap</i> deficiency, but not notochord formation. Therefore, mechanotransduction via Yap activation acts in feedforward mechanisms to induce <i>FoxA2</i> expression for notochord formation and activate <i>Shh</i> expression for floor plate induction by synergistically interacting with FoxA2.