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bioRxiv · 10.1101/2023.03.02.530846

FK506 binding protein 5 regulates cell quiescence-proliferation decision in zebrafish epithelium

Li, Y.·Liu, C.·Bai, X.·Li, M.·Duan, C.
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Abstract

The cell proliferation-quiescence decision plays fundamental roles in tissue formation and regeneration, and its dysregulation can lead to human diseases. In this study, we performed transcriptomics and genetic analyses using a zebrafish model to identify pathways and genes involved in epithelial cell quiescence-proliferation regulation. In this in vivo model, a population of GFP-labeled epithelial cells known as ionocytes were induced to reenter the cell cycle by a physiological stress. Transcriptomics analysis identified 1168 genes up-regulated and 996 genes down-regulated in the reactivated cells. GO and KEGG pathway analyses revealed that genes involved in transcription regulation, cell cycle, Foxo signaling, and Wnt signaling pathway are enriched among the up-regulated genes, while those involved in ion transport, cell adhesion, and oxidation-reduction are enriched among the down-regulated genes. Among the top up-regulated genes is FK506 binding protein 5 (Fkbp5), a member of the conserved immunophilin family. CRISPR/Cas9-mediated Fkbp5 deletion abolished ionocyte reactivation and proliferation. Pharmacological inhibition of Fkbp5 had similar effects. Further analyses showed that genetic deletion and inhibition of Fkbp5 impaired Akt signaling. Forced expression of a constitutively active form of Akt rescued the defects caused by Fkbp5 inhibition. These results uncover a previously unrecognized role of Fbkp5 in regulating the quiescence-proliferation decision via Akt signaling. Impact StatementTranscriptomic and genetic deletion studies unravel a new role of Fkbp5 in promoting cell reactivation via Akt signaling. HighlightsO_LITranscriptomic analysis reveals several molecular pathways altered during epithelial cell quiescence-proliferation transition. C_LIO_LIFkbp5 is highly up-regulated in reactivated and dividing cells. C_LIO_LIFkbp5 promotes epithelial cell reactivation and proliferation via Akt signaling. C_LI

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Li, Y., Liu, C., Bai, X., Li, M., Duan, C.. 2023-03-02. FK506 binding protein 5 regulates cell quiescence-proliferation decision in zebrafish epithelium. https://doi.org/10.1101/2023.03.02.530846

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