CiliaryTip · The role of ciliary tip organization in hedgehog signaling
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2020-07-01 → 2022-06-30
- EU contribution
- €145,941
- Participants
- 1
- Scheme
- MSCA-IF
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Results in brief
The role of ciliary tip organization in hedgehog signaling
This project examined the role of ciliary microtubule organization in hedgehog signaling. Cilia are essential motile and sensory organelles, with a sophisticated microtubule-based core structure (called the axoneme). The axoneme is made of compound outer microtubules that transition from a triplet organization at the base (A-, B- and C-tubules), to doublet organization in the middle segment (A- and B-tubules) and singlet organization (A-tubules) near the distal end of the cilium. These structural changes define the cilium geometry and correlate with the compartmentalization of various processes. Three proteins are so far known to control the length of ciliary microtubules in the protist Tetrahymena (CEP104, ARMC9 and CHE-12). Defects in these proteins affect hedgehog signaling in cell culture and in humans they cause a subset of cases of Joubert Syndrome, a neurodevelopmental ciliopathy. This raises the possibility that the ciliary geometry is important for hedgehog signaling and embryonic development. To test this, we examined the ciliary microtubule organization in the absence and presence of hedgehog signaling and the role of CEP104 and ARMC9 in hedgehog signaling and Xenopus embryonic development. We found that B-tubules terminate closer to each other in the absence of hedgehog signaling confirming the presence of a link between the cilium geometry and signaling. We also found that the role of CEP104 and ARMC9 in controlling the length of ciliary microtubules is conserved in vertebrates. We uncovered non-ciliary roles for CEP104 and show that defects in CEP104 and ARMC9 lead to the development of hedgehog related phenotypes and neurodevelopmental abnormalities in Xenopus.
Data: CORDIS, © European Union
Project objective
Cilia are microtubule-based organelles with essential motile, sensory and signaling functions. The cilium structure is important for its function however the mechanisms underlying the structure-function relationship are not well understood. The proposed study will address the role of the cilium structure in hedgehog signaling, one of the main cilia-based signaling pathways, essential for embryonic development and implicated in disease. In mammals, cilia are required for hedgehog signaling and the localization of signaling proteins at the distal end of cilia, the ciliary tip, is important for pathway activation. Structural defects at the ciliary tip affect the localization of signaling proteins and pathway activation and cause a subset of cases of Joubert Syndrome. We propose an unbiased and comprehensive approach to elucidate how the ciliary tip organization supports the localization and dynamics of hedgehog signaling proteins at this compartment. This work will impact how we address hedgehog related diseases in the future and will generate insights with broader implications with respect to the signaling and sensory roles of cilia. The fellow will conduct this work in the laboratory of Dr. Skourides at the University of Cyprus, a group with a consistent record of high quality publications, including important findings related to cilia. The Fellow’s experience in studying the ciliary tip in motile cilia and the expertise of the host in cellular and developmental biology ensure the successful implementation of the proposed work. The Fellow has demonstrated great potential in becoming an independent scientist by securing funding for her PhD work and receiving the Seal of Excellence on an MSCA-IF submitted in 2018. Through this fellowship the researcher will acquire both the training and experience that will allow her to transition to an independent career focused on the connection between cilium structure and function and its role in vertebrate development.
Original text from CORDIS.
Participants
- UNIVERSITY OF CYPRUS · NicosiaCoordinatorCyprus
Links
Data: CORDIS, © European Union