The long-term goal of our research is to understand, at molecular, cellular and developmental levels, how the cytoskeleton is organized and interacts with organelles, and how their interplay contributes to normal physiology and disease such as cancer and neurodegenerative disorders. We are particularly interested in microtubules and the Golgi apparatus, as these two essential cellular structures work coordinately in a variety of biological processes, including cell division, cell migration, ciliogenesis and neuronal development.
Currently our research focus is to investigate how the microtubules are robustly generated in vivo, either through de novo assembly (i.e. nucleation) from the building block tubulins, or via severing and branching (i.e. amplification) of existing microtubules.
Microtubule nucleation requires a highly conserved protein complex called the γ-tubulin ring complex (γ-TuRC). We aim to decipher the mechanisms of γ-TuRC assembly, targeting and activation using interdisciplinary approaches, including cryo-EM, biochemical purification, subcellular fractionation, proximity labeling with quantitative mass spectrometry, CRISPR-mediated genome editing and cell line engineering, esiRNA gene silencing combined with high-throughput screening, as well as advanced super-resolution and live cell imaging.
Disorganized microtubule network has been linked to a broad spectrum of neurogenesis abnormalities, neurodegenerative and muscular disorders. For instance, the genetic cause of MCD (malformations of cortical development) has been traced to γ-tubulin, the key factor responsible for nucleating microtubules in vivo. Furthermore, HSP (hereditary spastic paraplegia) is also linked to defects in microtubule cytoskeleton. Using primary neuronal culture and mouse models, we aim to dissect how microtubule nucleation, severing and branching regulate neuronal morphogenesis and brain development, and whether their dysregulation contributes to pathological phenotypes observed in developmental diseases and neurodegenerative disorders.
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