Professor, Cancer Cell Signaling Program, Cell Biology
- BS, Biochemistry, Beijing University
- PhD, Biology, Massachusetts Institute of Technology
- Postdoc, Developmental Neurobiology, University of California, San Francisco
University of Virginia Health System, P.O. Box 800732,
Pinn Hall, Room 3025
Charlottesville, Virginia 22908
Biophysics, Biotechnology, Cancer Biology, Cell and Developmental Biology, Genetics, Infectious Diseases/Biodefense, Microbiology, Molecular Biology, Neuroscience, Structural Biology, Translational Science
Wnt/PCP signaling in inner ear development Mouse models for human deafness Wnt/PCP signaling in neural tube closure
1. Wnt and PCP signaling in mechanosensory hair cell polarity.
The actin-based hair bundle atop sensory hair cells is the mechanotransduction organelle essential for hearing and balance. A majority of sensorineural hearing loss (SNHL) disorders, including hereditary deafness, are caused by defects in the development or maintenance of the hair bundle. We investigate mechanisms underlying planar polarization of hair cells, which is crucial for the organization and orientation of the hair bundle. Our work in the last decade has provided fundamental new insights into a microtubule-based hair cell-intrinsic polarity machinery as well as intercellular Planar Cell Polarity (PCP) signaling for aligning hair cell orientation. Recently, we have uncovered a novel Wnt / heterotrimeric G protein / PI3K signaling pathway important for hair bundle morphogenesis This non-canonical Wnt signaling pathway coordinates cell-intrinsic and tissue-level PCP via multiple effectors, including PI3K, Rac1 and Gsk3b JCB 2020, Frontiers in Cell and Dev Biology, 2021). Current projects aim to elucidate the signal transduction machinery and downstream targets of the Wnt/G protein signaling pathway.
2. Innervation of auditory hair cells by spiral ganglion neurons.
Our sense of hearing is critically dependent on the spiral ganglion neurons (SGNs), which are biopolar afferent neurons that transmit sound information received by hair cells to the central nervous system. During development, SGNs establish highly stereotyped connections with hair cell targets in the auditory sensory epithelium. Multiple type I SGNs innervate each inner hair cells to transmit sound signals, while type II SGNs innervate multiple outer hair cells to detect acoustic trauma. Recent findings suggest that PCP signaling is involved in the guidance of type II SGN peripheral projections. We are interested in identifying the axon guidance cues generated by the cochlear epithelium and how they are regulated by PCP signaling. Loss of functional connections between SGNs and HCs underlie hearing impairments caused by both genetic and environmental factors. Therefore, understanding the developmental programs that establish the highly stereotyped wiring patterns in the cochlea is crucial for circuit repair and regeneration following damage.
3. PCP signaling and biomechanical regulation of neural tube closure.
We previously identified Ptk7, which encodes a receptor pseudokinase, as a key regulator of PCP and actomyosin contractility in multiple types of developing epithelia, such as the neural tube and the inner ear sensory epithelia. Ptk7 mutations have been identified in human patients with neural tube defects (NTD). However, how Ptk7 couples actomyosin contractility with the generation of planar polarity during neural tube morphogenesis is poorly understood. In collaboration with Dr. Ann Sutherland in the department, we leverage a CRISPR-generated Ptk7 allelic series carrying NTD patient variants and fluorescence imaging of cytoskeletal and Rho GTPase dynamics in intact live mouse embryos to understand biomechanical mechanisms crucial for neural tube morphogenesis.