Guest Speaker: Dr. Yingzi Yang

Yap-mediated mechanotransduction in disease and development

ABSTRACT

My lab is interested in understanding how cell-cell signaling regulates both embryonic morphogenesis and adult physiology and how disruption of such signaling regulation leads to various diseases. After studying biochemical signaling pathways mediated by Wnts and Hedgehogs in skeletal biology and diseases for decades, we are also investigating biophysical pathway, particularly the Piezo/Hippo/Yap pathway in mechanotransduction, as cells experience and respond to both biochemical and mechanical signals throughout embryonic development and adult homeostasis. Bone and liver represent a hard and soft tissue, respectively, and they are critically controlled by their mechanoenvironment. Although the significance of mechanotransduction—the process by which mechanical forces are converted into biological cues—has been acknowledged since the 19th century, only recent advances have begun to reveal the molecular underpinnings bridging biophysical stimuli and gene regulation. Our studies in bone and liver biology and diseases reveal that cells adapt to their distinct mechanoenvironment by differentially controlling their normal ranges of YAP/TAZactivities, deviation from which causes diseases.

Identifying the cellular and molecular mechanisms underlying genetic diseases provides invaluable insights into normal functions of genes and signaling pathways. By understanding genetic forms of heterotopic ossification (HO), which is pathological bone formation in soft tissues, we identified a self-amplifying, self-propagating loop of Yesassociated protein (YAP)–Sonic hedgehog (SHH) as a core molecular mechanism underlying diverse forms of HO. This self-propagating positive feedback loop was both necessary and sufficient for HO expansion and could act independently of Gnas in fibrodysplasia ossificans progressiva (FOP), another genetic HO, and nonhereditary HO mouse models. Genetic or pharmacological inhibition of YAP or SHH abolished HO without affecting normal bone homeostasis, providing a previously unrecognized therapeutic rationale to prevent, reduce, and shrink HO. We then went on to show that in the developing neural tube (NT), Yap, a key mechanosensor and mechanotransducer, is both necessary and sufficient 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 FoxA2 and Shh expression. Mechanotransduction via Yap activation acts in feedforward mechanisms to induce FoxA2 expression for notochord formation and activate Shh expression for floor plate induction by synergistically interacting with FoxA2.