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Analysis of the role of Wnt signaling activation in ciliogenesis

Yuan, Cheng

[thumbnail of Thesis Cheng Yuan2022 final.pdf] PDF, English
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Wnt signaling pathways play an important role in a variety of cellular processes such as embryonic development, tissue homeostasis, and regeneration. Abnormal activation or inactivation of Wnt signaling leads to several diseases. Primary cilia functions as a key center of signaling transduction in vertebrate cells and, therefore, defects of primary cilia result in disorganized signaling transduction. Previous studies found that the primary cilia have been implicated in negative regulation of the canonical Wnt signaling. On the other hand, numerous Wnt components are found localized at the centrosome or basal body and involved in primary cilium formation. However, whether and how Wnt signaling regulates primary cilia formation is still poorly understood. In my study, I observed Wnt/β catenin signaling is active under primary cilia-inducing conditions by using the RPE1 7TGC Wnt reporter cell line. However, Wnt signaling's high activation could regulate primary cilia formation. Moreover, Wnt signaling highly activation-induced longer cilia formation. Because canonical Wnt signaling activates the transcriptional co-factor β catenin and LEF/TCF family of transcription factors to trigger gene expression, I also knockdown of TCF7 and found that Wnt/LRP6 signaling inhibits ciliogenesis independently of β catenin transcriptional regulation. By directly inhibiting GSK3β activity, I observed Wnt signaling suppresses cilia formation through GSK3β but in an indirect way. Because the downstream events of Wnt signaling also include β-catenin dependent signaling events, I observed Wnt signaling activated the downstream Wnt/TOR signaling. Moreover, inhibition of Wnt/TOR signaling by using rapamycin treatment rescued the cilia loss phenotype upon activation of Wnt signaling. Furthermore, I observed activation of Wnt/TOR signaling attenuated autophagy activity. Since autophagy degrades centriolar satellite OFD1 a negative regulator of primary cilia formation to promote ciliogenesis, I also depleted the autophagy targeting gene OFD1. Depletion of OFD1 rescued the cilia loss phenotype upon activation of Wnt signaling. Based on these results, I proposed that activation of Wnt signaling suppresses ciliogenesis towards autophagy by inhibiting degradation of OFD1 at the centriolar satellites.

Document type: Dissertation
Supervisor: Pereira, Prof. Dr. Gislene
Place of Publication: Heidelberg
Date of thesis defense: 1 April 2022
Date Deposited: 03 May 2022 13:13
Date: 2023
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
DDC-classification: 570 Life sciences
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