Research Lab

Primary cilium and mammalian neurodevelopment

Primary cilium is a solitary, microtubule-based organelle that extends from the cellular membrane and is found in most mammalian cell types, including neuronsand glial cells.This organelle serves as an antenna for signal transduction, hosting various receptors that transmit extracellular stimuli to intrinsic effectors, thereby supporting normal cellular function. Primary cilium plays a crucial role in mammalian neurodevelopment by regulating multiple pathways, including Sonic Hedgehog, Wnt, Notch, and TGFβ signaling. Disruption of primary cilium in neurons and glial cells impairs normal brain development. My research group aims to investigate the functions of primary cilia in neurons and glial cells and elucidate the mechanisms underlying their roles in mammalian neurodevelopment. We employ human stem cell-derived co-culture and organoid models, coupled with cell biology, neurophysiology, and bioinformatics approaches to provide mechanistic insights.

The role of primary cilium in neurological disorders

Mutations in primary cilium-associated genes have been linked to neurodevelopmental disorders in humans. My research group has used genome editing techniques to introduce specific mutations into human induced pluripotent stem cells (iPSCs). These mutant iPSCs are subsequently differentiated into neuronal models to assess the impact of ciliary dysfunction on neurodevelopment. Additionally, ciliary defects have been implicated in adult-onset neurodegenerative diseases. To further investigate the pathogenic role of primary cilium, we have generated patient iPSCs, which are in turn differentiated into disease-relevant neuronal subtypes. These models allow us to dissect the mechanisms by which ciliary deficits contribute to disease pathogenesis.Our work aims to uncover the role of primary cilium in both neurodevelopmental and neurodegenerative disorders, providing a potential new target for disease-modifying therapy.

1. Chen, Z.S.*, Peng, S.I.*, Leong, L.I., Gall-Duncan, T., Wong, N.S.J., Li, T.H., Lin, X., Wei, Y., Koon, A.C., Huang, J., Sun, J.K.L., Turner, C., Tippett, L., Curtis, M.A., Faull, R.L.M., Kwan, K.M., Chow, H.M., Ko, H., Chan, T.F., Talbot, K., Pearson, C.E. and Chan, H.Y.E. Mutant huntingtin induces neuronal apoptosis via derepressing the non-canonical poly(A) polymerase PAPD5. (Preprint: https://doi.org/10.21203/rs.3.rs-2983878/v1)
2. Chen, Z.S., Ou, M., Taylor, S., Dafinca, R., Peng, S.I., Talbot, K. and Chan, H.Y.E. (2023) Mutant GGGGCC RNA prevents YY1 from binding to Fuzzypromoter which stimulates Wnt/β-catenin pathway in C9ALS/FTD. Nat. Commun. 14(1), 8420.
3. Chen, Z.S., Yan, M., Pei, W., Yan, B., Huang, C. and Chan, H.Y.E. (2022) Lignin-carbohydrate complexes suppress SCA3 neurodegeneration via upregulating proteasomal activities. Int. J. Biol. Macromol. 218, 690-705.
4. Chen, Z.S., Huang, X., Talbot, K. and Chan, H.Y.E. (2021) A fine balance between Prpf19 and Exoc7 in achieving degradation of aggregated protein and suppression of cell death in spinocerebellar ataxia type 3. Cell Death Dis. 12(2), 136.
5. Chen, Z.S., Li, L., Peng, S., Chen, F.M., Zhang, Q., An, Y., Lin, X., Li, W., Koon, A.C., Chan, T.F., Lau, K.F., Ngo, J.C.K., Wong, W.T., Kwan, K.M. and Chan, H.Y.E. (2018) Planar cell polarity gene Fuztriggers apoptosis in neurodegenerative disease models. EMBO Rep. 19(9), e45409.