Mechanisms of cilia biogenesis and signalling
Cilia are sensory organelles that detect mechanical and chemical stimuli from the environment. They arise from centrioles and function as “antennae” that receive and integrate extracellular signals. The Hedgehog pathway, a developmental pathway implicated in cancer, is one important example of a signalling pathway whose function depends on the presence of primary cilia. Primary cilia are present in almost every cell, and their disruption results in a number of illnesses called ciliopathies which include retinal degeneration, obesity, diabetes and polycystic kidney disease. Previously, we identified a novel group of centriolar distal appendage proteins (DAPs) and defined their role in ciliogenesis (Tanos et al, 2013, Yang et al, 2018). These proteins now have been shown to be mutated in diverse ciliopathies including infantile nephronophthisis, intellectual disability (Failler et al), and oro-facio-digital syndrome type IX featuring midline cleft, microcephaly, and colobomatous microphathalmia/anophthalmia (Adly et al 2014). Thus, to better understand the molecular basis of these diseases, it is critical to understand how centrioles promote ciliogenesis and how they regulate ciliary signalling. Recently, we have shown that a centriolar kinase, TTBK2, supports ciliary vesicle formation and ciliary assembly (Lo et al, 2019) and have also demonstrated a role for primary cilia in drug resistance in cancer (Jenks et al, 2018).
The objectives of this project are to understand the molecular complexes that regulate cilia biogenesis and signalling and to understand how their misregulation can lead to disease. We will focus on the regulation of centriole distal appendage proteins (DAPs).
We will use CRISPR/Cas9-engineered isogenic cell lines deficient in specific centriolar proteins, including DAPs, to understand how they are recruited to centrioles and how they regulate ciliogenesis. To this end, we will use various biochemical, cell biology and microscopy techniques. We will have access to animal models in collaboration with a number of labs at Brunel. At the end of the project the student will have developed tools to carry out research independently, and have substantial practical and conceptual knowledge of the cilia field.
Barbara E. Tanos, Hui-Ju Yang, Rajesh Soni, Won-Jing Wang, Frank P. Macaluso, John M. Asara and Meng-Fu Bryan Tsou.Centriole distal appendages promote membrane docking, leading to cilia initiation. 2013. Genes Dev 27: 163-168.
T. Tony Yang, Weng Man Chong, Won-Jing Wang, Gregory Mazo, Barbara Tanos, Zhengmin Chen, Thi Minh Nguyet Tran, Yi-De Chen, Rueyhung Roc Weng, Chia-En Huang, Wann-Neng Jane, Meng-Fu Bryan Tsou, Jung-Chi Liao. Architecture of mammalian centriole distal appendages supports a matrix that gates the primary cilium. 2018. Nature Communications. 2018 May 22;9(1):2023. doi: 10.1038/s41467-018-04469-1. doi: https://doi.org/10.1101/193474
Failler M, Gee HY, Krug P, Joo K, Halbritter J, Belkacem L, Filhol E, Porath JD, Braun DA, Schueler M, Frigo A, Alibeu O, Masson C, Brochard K, Hurault de Ligny B, Novo R, Pietrement C, Kayserili H, Salomon R, Gubler MC, Otto EA, Antignac C, Kim J, Benmerah A, Hildebrandt F, Saunier S. Mutations of CEP83 cause infantile nephronophthisis and intellectual disability. Am J Hum Genet. 2014 Jun 5;94(6):905-14. doi: 10.1016/j.ajhg.2014.05.002. Epub 2014 May 29. PMID: 24882706.
Adly N, Alhashem A, Ammari A, Alkuraya FS. Ciliary genes TBC1D32/C6orf170 and SCLT1 are mutated in patients with OFD type IX. Hum Mutat. 2014 Jan;35(1):36-40. doi: 10.1002/humu.22477.
Chien-Hui Lo, I-Hsuan Lin, T. Tony Yang, Yen-Chun Huang, Barbara E. Tanos, Yeou-Guang Tsay, Jung-Chi Liao and Won-Jing Wang. TTBK2 phosphorylates CEP83 in promoting cilia initiation. 2019. Journal of Cell Biology. 2019 Aug 27. PMID:31455668
Andrew D. Jenks, Simon Vyse, Jocelyn P. Wong, Deborah Keller, Tom Burgoyne, Amelia Shoemark, Maike de la Roche, Martin Michaelis, Jindrich Cinatl, Paul H. Huang and Barbara E. Tanos. Primary cilia mediate diverse kinase inhibitor resistance mechanisms in cancer. 2018. 2018. Cell Reports. 2018 Jun 5;23(10):3042-3055. doi: 10.1016/j.celrep.2018.05.016.
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This is a self funded topic
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