CtBP impedes JNK- and Upd/STAT-driven cell fate misspecifications in regenerating Drosophila imaginal discs

Abstract

Regeneration following tissue damage often necessitates a mechanism for cellular re-programming, so that surviving cells can give rise to all cell types originally found in the damaged tissue. This process, if unchecked, can also generate cell types that are inappropriate for a given location. We conducted a screen for genes that negatively regulate the frequency of notum-to-wing transformations following genetic ablation and regeneration of the wing pouch, from which we identified mutations in the transcriptional co-repressor C-terminal Binding Protein (CtBP). When CtBP function is reduced, ablation of the pouch can activate the JNK/AP-1 and JAK/STAT pathways in the notum to destabilize cell fates. Ectopic expression of Wingless and Dilp8 precede the formation of the ectopic pouch, which is subsequently generated by recruitment of both anterior and posterior cells near the compartment boundary. Thus, CtBP stabilizes cell fates following damage by opposing the destabilizing effects of the JNK/AP-1 and JAK/STAT pathways.

The transcriptional co-repressor CtBP is a negative regulator of growth that antagonizes the Yorkie and JNK/AP-1 pathways

“…Previously, while characterizing the role of CtBP in regulating regenerative plasticity, our group reported that loss of CtBP function results in the upregulation of several reporters of AP-1 activity (Worley et al, 2018), suggesting that JNK and CtBP may have opposing effects on shared transcriptional targets (Figure 5A). Since we have demonstrated the minimal ban enhancer is activated by JNK signaling, we hypothesized that CtBP may normally antagonize this effect, which could explain why brC12-lacZ expression is increased in CtBP mutant tissue.…”

“…We had previously identified CtBP, which encodes a transcriptional corepressor, in a screen for genes that regulate regenerative plasticity (Worley et al, 2018). In a separate screen, we identified an allele of CtBP as a mutation that enables mutant cells to outgrow their wild-type neighbors.…”

Reflections on Bateson's rule: Solving an old riddle about why extra legs are mirror‐symmetric

“…Evidence was then beginning to accumulate that apoptosis can cause cells to change their identity before they expire (Szabad, Simpson, & Nöthiger, ), and the case has grown stronger since then (Worley, Alexander, & Hariharan, ), so Meinhardt simply connected all of these dots: (a) the mutation causes curved zones of cell death (Figure b), (b) the cells in such an A zone could switch identity from A to P, in which case (c) a thick arc of P cells might now overlap the AD/AV boundary (Figure c), and if so, then (d) two new AD/AV/P intersection points would ensue, and (e) two new legs would branch out (Figure d). He explained that the legs are mirror symmetric because the clockwise or counterclockwise (P→AV→AD) order of the areas around the intersection point would dictate each leg's handedness.…”

“…Evidence was then beginning to accumulate that apoptosis can cause cells to change their identity before they expire (Szabad, Simpson, & Nöthiger, 1979), and the case has grown stronger since then (Worley, Alexander, & Hariharan, 2018), so Meinhardt simply connected all of these dots: (a) the mutation causes curved zones of cell death ( Figure 6b Despite the elegance of Meinhardt's model, it lacked enough supporting evidence to be widely accepted at the time (Marsh & Theisen, 1999). Nevertheless, its fortunes were about to change.…”

“…The solution to this paradox appears to be that apoptosis induces amnesia before it delivers the coup de grace: it causes cells to "forget" who they are by erasing memory markers (polycomb proteins, etc.) from their identity genes (Worley et al, 2018). Thus, a cluster of cells in the Dpp sector, say, could forget its Dpp identity and "re-boot" in either its old Dpp state or a new Wg one (Morata, Shlevkov, & Pérez-Garijo, 2011).…”