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Balancing the distal tip length of primary cilia is essential for keeping their signaling function in mammalian cells

Kanamaru, Taishi

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Abstract

Sensing signals from the extracellular environment is one of the most important and fundamental biological processes. Primary cilia are highly conserved antenna-like organelles, which are perceiving chemical and biological molecules for signal transduction. Primary cilia are required for several signalling pathways such as Sonic hedgehog (Shh), Wnt, and mTOR. Thus, defective mutations of cilia component affect signal transduction, causing severe body developmental errors that are categorized as genetic diseases called ciliopathies. Previous studies have shown that abnormally extended primary cilia in ciliopathy patient cells result in lower signalling response. That is why, controlling the cilia length is essential for maintaining their signalling function, but this mechanism is still not completely understood yet.

In my PhD study, I would like to propose one of the reasons why over-elongated cilia in mammalian cells drop the ability of signal transduction. I observed that the middle/distal cilia segmentation is conserved in mammalian cells as the same as the lower eukaryotes. It is known that the middle segment stabilizes cilia structure and the distal segment contributes as the ciliary signalling scaffold. After the small-scale loss of function screening, I have identified Septin as a negative regulator of the distal segment growth. Septin is a fibre-like protein localizing at cilia to regulate the formation of the transition zone, which is a protein complex at the base of cilia passing the cilia-building blocks to cilia selectively like a gatekeeper. A functional transition zone allows transferring a ciliary capping kinesin KIF7 at the cilia tip to suppress the distal segment growth. Moreover, over-elongated distal segment lost the ability of constant cilia length maintenance that leads to a high incidence of cilia excision. The cilia excision event reduces the amount of intermediate Shh pathway factors such as Sufu and Glis at the distal cilia tip. Therefore, cells with over-elongated distal segments fail to upregulate Shh signal transduction.

Finally, I strongly believe that this study opens up the cilia field by elucidating the link between primary cilia segmentation and signalling function in mammalian models.

Item Type: Dissertation
Supervisor: Pereira, Prof. Dr. Gislene
Place of Publication: Heidelberg
Date of thesis defense: 27 July 2021
Date Deposited: 16 Aug 2021 08:30
Date: 2022
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Service facilities > Centre for Organismal Studies Heidelberg (COS)
Service facilities > German Cancer Research Center (DKFZ)
Subjects: 000 Generalities, Science
570 Life sciences
Uncontrolled Keywords: Primary cilia, Cell biology, Signalling pathway
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