Ph.D. Human Genetics, Yale University
Centrioles/Centrosomes, Cilia, Neural Stem Cells, and Tumorigenesis
Centrioles are essential components of the centrosomes, which are required for the formation of the mitotic spindles, cilia, and flagella. Centriole duplication involves the growth of a procentriole (daughter centriole) from an existing centriole (mother centriole). Primary microcephaly (MCPH) is characterized by a substantial reduction in size of the cerebral cortex with mild to severe mental retardation. Recently, mutations in many centriolar genes have been reported to cause MCPH and ciliopathies, but their underlining mechanisms remain incompletely understood. During the past years, my lab has identified several key proteins that participate in centriole duplication and cilia formation. We found that CPAP cooperates with CEP120 to regulate centriole length (Nat Cell Biol. 2009; J Cell Biol 2013; Sci Rep 2019). We further demonstrated that CPAP and STIL could interact with each other (EMBO J, 2011) and form complexes with CEP135 (EMBO J, 2013), CEP120 (J Cell Biol, 2013), and RTTN (Nat Commun, 2017), and such interactions are critical to build a full-length centriole. Interestingly, mutations in CPAP, STIL, CEP135, and RTTN genes cause primary microcephaly, and complete loss of CPAP produces severe and neurological phenotypes in developing mouse brain (J Cell Sci, 2020). Our findings support a concept that defect in centriole biogenesis is one of main causes for MCPH. In addition, we also found that Myosin-Va mediates the initial transportation of preciliary vesicles to the mother centriole, that defines the onset of ciliogenesis (Nat Cell Biol 2018). Recent reports showed that uncontrolled centriole/centrosome replication might lead to unrestrained proliferation and chromosome instability in cancers. We will use a combination of molecular and cellular, genetic, animal model, and hiPSC-derived organoid approaches to understand how the cellular organelles (centrioles or cilia) are established and how mutations in centriolar genes cause primary microcephaly, ciliopathies, and tumorigenesis in humans.
A novel HIF1α-STIL-FOXM1 axis regulates tumor metastasisJournal of Biomedical Science, Apr 01, 2022
Modeling Human Primary Microcephaly With hiPSC-Derived Brain Organoids Carrying CPAP-E1235V Disease-Associated Mutant ProteinFrontiers in Cell and Developmental Biology, Mar 02, 2022