Mashanov V et al. (2020), Active Notch signaling is required for arm rege...

ECB-ART-49835

PLoS One 2020 May 12;155:e0232981. doi: 10.1371/journal.pone.0232981.

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Active Notch signaling is required for arm regeneration in a brittle star.

Mashanov V , Akiona J , Khoury M , Ferrier J , Reid R , Machado DJ , Zueva O , Janies D .

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Cell signaling pathways play key roles in coordinating cellular events in development. The Notch signaling pathway is highly conserved across all multicellular animals and is known to coordinate a multitude of diverse cellular events, including proliferation, differentiation, fate specification, and cell death. Specific functions of the pathway are, however, highly context-dependent and are not well characterized in post-traumatic regeneration. Here, we use a small-molecule inhibitor of the pathway (DAPT) to demonstrate that Notch signaling is required for proper arm regeneration in the brittle star Ophioderma brevispina, a highly regenerative member of the phylum Echinodermata. We also employ a transcriptome-wide gene expression analysis (RNA-seq) to characterize the downstream genes controlled by the Notch pathway in the brittle star regeneration. We demonstrate that arm regeneration involves an extensive cross-talk between the Notch pathway and other cell signaling pathways. In the regrowing arm, Notch regulates the composition of the extracellular matrix, cell migration, proliferation, and apoptosis, as well as components of the innate immune response. We also show for the first time that Notch signaling regulates the activity of several transposable elements. Our data also suggests that one of the possible mechanisms through which Notch sustains its activity in the regenerating tissues is via suppression of Neuralized1.

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	Fig 1. Effect of DAPT (3 μM) treatment on the structure of the regenerating arm (day 14 post-autotomy).A—A ′″: Aboral view of regenerating arms from four representative control animals exposed to DMSO (vehicle). Two arms from each animal are shown. B—B′″: Aboral view of regenerating arms from four representative animals exposed to 3 μM DAPT. Two arms from each animal are shown. C and D: Representative sagittal sections through the regenerating arm of a control (DMSO-treated) individual (C) and a DAPT-treated individual (D). Hematoxylin and eosin staining. Arrowheads show the arm outgrowth (regenerate). Dashed lines show the position of the autotomy plane. Abbreviations: ac—arm coelom; rnc—radial nerve cord; rvc—radial canal of the water-vascular system.
	Fig 2. Boxplots showing the effect of DAPT (3 μM) treatment on the length of the outgrowth (A) and the number of segments in the regenerating arm (B). By day 14 post-autotomy, the DAPT treatment significantly reduced both the total length of the outgrowth (by the factor of 1.6, T-test p-value = 0.002) and the number of segments in the new arm (by the factor of 1.4, T-test p-value = 0.047).
	Fig 3. Differentially expressed genes in the DAPT-treated animals as compared to the control (DMSO-treated) cohort.Volcano plot showing the log2 fold change on the X-axis and -log10 of adjusted p-values on the Y-axis. The significantly up-regulated transcripts (red) are to the right, and significantly down-regulated transcripts (blue) are to the left. Each gene is represented with a dot. Grey dots represent the genes whose expression level did not change significantly in response to DAPT treatment. The differentially expressed contigs were defined as those whose associated adjusted p-value was less than 0.05 and the log2 fold change in expression exceeded ±0.58. Volcano plot showing the log2 fold change on the X-axis and -log10 of adjusted p-values on the Y-axis. Each gene is represented with a dot. The 1,978 significantly up-regulated transcripts (red) are to the right, and the 2,434 significantly down-regulated transcripts (blue) are to the left. Grey dots represent the genes whose expression level did not change significantly in response to DAPT treatment. The differentially expressed contigs were defined as those whose associated adjusted p-value was less than 0.05 and the log2 fold change in expression exceeded ±0.58.). Boxed labels represent UniProt IDs (with label copy number within parenthesis) shown in Tables 2 and 3.

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