Associate Professor, Cell Biology
- BS, Biochemistry, Beijing University
- PhD, Biology, Massachusetts Institute of Technology
- Postdoc, Developmental Neurobiology, University of California, San Francisco
Biophysics, Biotechnology, Cancer Biology, Cell and Developmental Biology, Genetics, Infectious Diseases/Biodefense, Microbiology, Molecular Biology, Neuroscience, Structural Biology, Translational Science
Developmental regulation of planar cell polarity in the mammalian nervous system
1. Cilia-mediated 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. In mammals, damaged hair bundles are repaired inefficiently, ultimately leading to permanent hearing loss. Therefore, a complete understanding of the developmental programs that orchestrate hair bundle morphogenesis in the mammalian cochlea is of high medical and translational importance.
Both intercellular and cell-intrinsic PCP signaling is critically important for normal hair bundle structure and orientation. The V-shaped hair bundle is comprised of rows of actin-based stereocilia tethered to the kinocilium, the hair cell primary cilia, at the vertex. In addition to a structural role, we have discovered a novel signaling role of the kinocilium in regulating hair cell PCP. We have identified a novel non-canonical Wnt signaling pathway that acts both at the apical cell cortex and in the kinocilium to mediate hair cell planar polarity. Current projects aim to elucidate the function and signal transduction mechanisms of this pathway, and whether this pathway can be re-activated in mature hair cells to promote hair bundle repair and functional regeneration.
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 Wnt ligands secreted by the epithelium and PCP signaling are involved in both guidance and synapse formation of the SGN peripheral projections. We are investigating how Wnt and PCP signaling direct SGN projection and target innervation.
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 actomyosin contractility in neural tube closure
We previously identified Ptk7, which encodes a receptor pseudokinase, as a key regulator of PCP signaling in vertebrates. In developing epithelia such as the neural tube and the cochlear duct, Ptk7 mediates anisotropic junctional contractility crucial for directional cell rearrangement. However, the underlying molecular mechanisms remain incompletely understood. Recently, PTK7 missense variants associated with human patients with neural tube defects have been reported. Leveraging these patient alleles, we have generated via CRISPR a panel of Ptk7 knockin mice carrying patient mutations and will correlate biochemical activity with cell behavior and mutant phenotypes to gain insights into the mechanisms of action for Ptk7 during neural tube closure.
A mechanistic understanding of the Ptk7-mediated signaling pathway for mammalian PCP regulation will provide important insights into how cytoskeletal asymmetry is precisely regulated in time and space to drive tissue morphogenesis. These insights are not only highly relevant for human development and birth defects, but also have broad implications for epithelial homeostasis and tumorigenesis.