Speaker

Professor Yingzi YANG

Professor of Developmental Biology
Harvard School of Dental Medicine
Harvard Stem Cell Institute
Dana-Farber / Harvard Cancer Center

Topic

Yap-mediated Mechanotransduction in Disease & 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/TAZ activities, deviation from which causes diseases. We further show that that in the developing neural tube (NT), Yap, a key mechanosensor and mechanotransducer, is both necessary and sufficient for the 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 induces FoxA2 and Shh expression, whereby establishing the ventral signaling center required for dorsal-ventral patterning of the trunk.

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 Yes- associated 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.

Biography

Professor Yingzi Yang is Associate Dean for Translational Research, Professor of Developmental Biology, and Director of Biological Sciences in Dental Medicine (BSDM) PhD Program at the Harvard School of Dental Medicine. Professor Yang completed her B.S. degree from the Fudan University in Shanghai, China, and trained in the U.S.studying Wnt and Hedgehog signaling in early limb patterning under the guidance of Dr. Lee Niswander at the Sloan-Kettering Cancer Institute, where she was awarded her Ph.D. in Molecular Biology by the Weill Medical College of Cornell University. She completed a postdoctoral fellowship in mammalian developmental biology and genetics in the laboratory of Dr. Andy McMahon at Harvard University. In 2000 she became an investigator at the Genetic Disease Research Branch of the National Human Genome Research Institute (NHGRI), focusing on skeletal biology. Yang was head of the Developmental Genetics Section and a senior investigator of NHGRI. She joined HSDM as Professor of Developmental Biology in 2014. Professor Yang has received many honors and awards during her scientific career. She is the recipient of Vincent du Vigneaud Award of Excellence from the Weill Medical College of Cornell University, Postdoctoral fellowship award from the Cancer Research Fund of the Damon Runyon-Walter Winchell Foundation, NIH Award of Merit, SCBA Young investigator award and NIH APAO Outstanding Achievements and Merit Scholarship Award.