Distinct signaling signatures drive compensatory proliferation via S-phase acceleration

Abstract

Regeneration relies on cell proliferation to restore damaged tissues. Multiple signaling pathways activated by local or paracrine cues have been identified to promote regenerative proliferation. How different types of tissue damage may activate distinct signaling pathways and how these differences converge on regenerative proliferation is less well defined. To better understand how tissue damage and proliferative signals are integrated during regeneration, we investigate models of compensatory proliferation in Drosophila imaginal discs. We find that compensatory proliferation is associated with a unique cell cycle profile, which is characterized by short G1 and G2 phases and, surprisingly, by acceleration of the S-phase. S-phase acceleration can be induced by two distinct signaling signatures, aligning with inflammatory and non-inflammatory tissue damage. Specifically, non-autonomous activation of JAK/STAT and Myc in response to inflammatory damage, or local activation of Ras/ERK and Hippo/Yki in response to elevated cell death, promote accelerated nucleotide incorporation during S-phase. This previously unappreciated convergence of different damaging insults on the same regenerative cell cycle program reconciles previous conflicting observations on proliferative signaling in different tissue regeneration and tumor models.

Mutual repression between JNK/AP-1 and JAK/STAT stratifies senescent and proliferative cell behaviors during tissue regeneration

“…We thus analyzed the ability of Stat92E to override the cell cycle arrest in the G2-phase. In undamaged control discs, targeted expression of Stat92E using rn- GAL4 altered the proportion of cells in S-phase consistent with its reported role in cell cycle acceleration [ 133 ], yet importantly, it did not alter the proportion of cells in G1 or G2 ( S7E–S7H Fig ) . In contrast, a cell cycle analysis of egr , Stat92E-HA coexpressing domains revealed a substantial increase in G1-phase cells, indicating that JNK-signaling cells did not stall in G2 anymore ( Fig 7J–7M ) .…”

“…The adult wing blade arising from the damaged wing pouch allows for assessment of regenerative success. (B’) Schematic of the FUCCI cell cycle indicator, utilizing the degradable mRFP-NLS-CycB 1-266 (red) and GFP-E2F1 1-230 (green) reporters as readouts for G1/late G2 and late S/G2 phases of the cell cycle, respectively [ 133 , 148 ]. Cells in the S-phase and M-phase are detected using EdU incorporation and pH3 staining, respectively.…”

Coordination of cell cycle and morphogenesis during organ formation

“…Given that apoptosis can induce compensatory cell proliferation in neighboring cells to maintain tissue homeostasis ( Haynie and Bryant, 1977 ; Kondo et al, 2006 ; Crucianelli et al, 2022 ), we investigated whether the abnormal cell division in hkb mutants was a result of apoptosis. The number of PH3-positive cells in p35-overexpressing SGs in hkb mutants was comparable to that in hkb mutants alone ( Figure 4J and M ), suggesting that the abnormal cell division in hkb mutants may not be compensatory cell proliferation induced by apoptosis.…”

Coordination of cell cycle and morphogenesis during organ formation

“…We observed an increase in F-actin along the apical junctions in PH3-positive SG cells (Figure 4L). Given that apoptosis can induce compensatory cell proliferation in neighboring cells to maintain tissue homeostasis (Haynie and Bryant, 1977;Kondo et al, 2006;Crucianelli et al, 2022), we investigated whether the abnormal cell division in hkb mutants was a result of apoptosis. The number of PH3-positive cells in p35-overexpressing SGs in hkb mutants was comparable to that in hkb mutants alone (Figure 4J, M), suggesting that the abnormal cell division in hkb mutants may not be compensatory cell proliferation induced by apoptosis.…”