Wang Zheng

Demystifying Mechanotransduction in Brain Development and Disorders

Mechanotransduction is a fundamental ability of cells to detect and respond to physical forces and is involved in a broad range of physiological processes, including sense of touch and hearing. Increasing evidence has been accumulated to demonstrate that mechanotransduction plays crucial roles in brain development and disruption of mechanotransduction can lead to severe developmental abnormalities and neurological disorders. The Zheng lab aims to uncover the cellular and molecular basis of mechanotransduction events during brain development.

We are currently focused on mechanosensitive TMEM63 ion channels, which are mutated in human neurological disorders. Particularly, TMEM63B mutations can cause severe early-onset developmental and epileptic encephalopathy, associated with progressive neurodegenerative brain changes. We seek to understand how TMEM63 ion channels can be activated by physical force using in vitro systems and then leverage this knowledge to reveal how force sensing of TMEM63s is related to their in vivo physiology and pathology in the brain. To achieve this, we employ a variety of cutting-edge techniques, including but not limited to single particle cryo-electron microscopy, confocal fluorescence microscopy, patch clamp electrophysiology, artificial lipid bilayer/nanodiscs reconstitution, mass spectrometry etc. We also use multiple genetically modified mouse models for in vivo studies. Together, we hope to gain insights into the function and dysfunction of mechanotransduction in brain development and to develop therapeutical strategies against developmental brain disorders by targeting mechanosensitive TMEM63 ion channels.