Research Project: Primer silyum, silyopatiler ve mikrotübül-ilişkili proteinler arasındaki moleküler ve fonksiyonel ilişkinin belirlenmesi
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Contributors
Funders
ID
TB.00572
Authors
Karalar, Elif Nur Fırat
Faculty Member
Publications
CCDC66 regulation of cytoskeleton and cilia stability is important for signaling and epithelial organization
(Public Library Science, 2025) Deretic, Jovana; Emek, Şeyma Cengiz; Seyrek, Ece; Karalar, Elif Nur Fırat; Emek, Şeyma Cengiz; Seyrek, Ece; Department of Molecular Biology and Genetics; School of Medicine; Yes; College of Sciences; SCHOOL OF MEDICINE
The primary cilium is a conserved, microtubule-based organelle that transduces signaling pathways essential for development and homeostasis. It dynamically assembles and disassembles in response to intrinsic and extrinsic stimuli while maintaining remarkable structural stability and tightly regulated length. The mechanisms underlying this stability and length control are not well understood. Here, we characterized CCDC66, a microtubule-associated protein linked to ciliopathies, as an important regulator of cilium maintenance and disassembly in mouse epithelial cells. Live imaging revealed that cilia in CCDC66-depleted cells frequently fluctuate in length and exhibit increased cilium disassembly and ectocytosis. Phenotypic rescue experiments and in vitro assays showed that microtubule stabilization activity of CCDC66 is required for these functions. Temporal proximity mapping identified potential new regulators and molecular pathways involved in cilium disassembly. Further characterization revealed actin cytoskeleton and vesicular trafficking as additional mechanisms by which CCDC66 may mediate its ciliary functions. Finally, depletion of CCDC66 compromised Hedgehog and Wnt pathway activation and disrupted epithelial cell organization and polarity in two- and three-dimensional cultures. Collectively, we showed that CCDC66 regulates both ciliary and non-ciliary processes through diverse mechanisms involving microtubules, actin, and vesicular trafficking, providing insights into the pathologies associated with CCDC66.
CCDC66 regulates primary cilium length and signaling via interactions with transition zone and axonemal proteins
(Company of Biologists, 2023) Odabaşı, Ezgi; Çonkar, Deniz; Deretic, Jovana; Batman, Umut; Karalar, Elif Nur Fırat; Frikstad, Kari-Anne M.; Patzke, Sebastian; Department of Molecular Biology and Genetics; Yes; College of Sciences
The primary cilium is a microtubule-based organelle that serves as a hub for many signaling pathways. It functions as part of the centrosome or cilium complex, which also contains the basal body and the centriolar satellites. Little is known about the mechanisms by which the microtubule-based ciliary axoneme is assembled with a proper length and structure, particularly in terms of the activity of microtubule-associated proteins (MAPs) and the crosstalk between the different compartments of the centrosome or cilium complex. Here, we analyzed CCDC66, a MAP implicated in cilium biogenesis and ciliopathies. Live-cell imaging revealed that CCDC66 compartmentalizes between centrosomes, centriolar satellites, and the ciliary axoneme and tip during cilium biogenesis. CCDC66 depletion in human cells causes defects in cilium assembly, length and morphology. Notably, CCDC66 interacts with the ciliopathy-linked MAPs CEP104 and CSPP1, and regulates axonemal length and Hedgehog pathway activation. Moreover, CCDC66 is required for the basal body recruitment of transition zone proteins and intraflagellar transport B (IFT-B) machinery. Overall, our results establish CCDC66 as a multifaceted regulator of the primary cilium and provide insight into how ciliary MAPs and subcompartments cooperate to ensure assembly of functional cilia.
The multifaceted roles of microtubule-associated proteins in the primary cilium and ciliopathies
(Company of Biologists Ltd, 2023) Deretic, Jovana; Karalar, Elif Nur Fırat; Odabaşı, Ezgi; Department of Molecular Biology and Genetics; Graduate School of Sciences and Engineering; Yes; College of Sciences; GRADUATE SCHOOL OF SCIENCES AND ENGINEERING
The primary cilium is a conserved microtubule-based organelle that is critical for transducing developmental, sensory and homeostatic signaling pathways. It comprises an axoneme with nine parallel doublet microtubules extending from the basal body, surrounded by the ciliary membrane. The axoneme exhibits remarkable stability, serving as the skeleton of the cilium in order to maintain its shape and provide tracks to ciliary trafficking complexes. Although ciliary trafficking and signaling have been exhaustively characterized over the years, less is known about the unique structural and functional complexities of the axoneme. Recent work has yielded new insights into the mechanisms by which the axoneme is built with its proper length and architecture, particularly regarding the activity of microtubule-associated proteins (MAPs). In this Review, we first summarize current knowledge about the architecture, composition and specialized compartments of the primary cilium. Next, we discuss the mechanistic underpinnings of how a functional cilium is assembled, maintained and disassembled through the regulation of its axonemal microtubules. We conclude by examining the diverse localizations and functions of ciliary MAPs for the pathobiology of ciliary diseases.
