Abstract
Larval tracheae of Drosophila harbour progenitors of the adult tracheal system (tracheoblasts). Thoracic tracheoblasts are arrested in the G2 phase of the cell cycle in an ATR (mei-41)-Checkpoint Kinase1 (grapes, Chk1) dependent manner prior to mitotic re-entry. Here we investigate developmental regulation of Chk1 activation. We report that Wnt signaling is high in tracheoblasts and this is necessary for high levels of activated (phosphorylated) Chk1. We find that canonical Wnt signaling facilitates this by transcriptional upregulation of Chk1 expression in cells that have ATR kinase activity. Wnt signaling is dependent on four Wnts (Wg, Wnt5, 6,10) that are expressed at high levels in arrested tracheoblasts and are downregulated at mitotic re-entry. Interestingly, none of the Wnts are dispensable and act synergistically to induce Chk1. Finally, we show that downregulation of Wnt signaling and Chk1 expression leads to mitotic re-entry and the concomitant upregulation of Dpp signaling, driving tracheoblast proliferation.
Highlights
The development of a single cell into an organism depends on cells dividing at the appropriate time and place
To explore the possibility that developmental signals control the activation of the ATR/Chk1 axis in tracheoblasts, we knocked-down expression of essential transducers of the EGF, FGF, insulin/PI3K, Hedgehog, JAK/STAT, Ecdysone, Notch, Wnt and Dpp signalling pathways in the trachea by RNA interference (under control of Breathless (Btl)-Gal4) and determined if these perturbations led to precocious mitotic re-entry at 16-24 h in L3
Since perturbations in Wnt signalling led to precocious proliferation akin to loss of Chk1, we examined the role of Wnt pathway with regard to Chk1 activation
Summary
The development of a single cell into an organism depends on cells dividing at the appropriate time and place. This requires that cells remain mitotically arrested for a period and resume cycling thereafter. Competent cells are known to pause either in the G1/G0(Cheung and Rando, 2013) or G2 (Bouldin and Kimelman, 2014) phases of the cell cycle. We investigate the mechanisms that regulate developmental G2 arrest. Mechanisms regulating developmental G2 arrest have been studied in Drosophila (Johnston and Edgar, 1998, Ayeni et al, 2016, Otsuki and Brand, 2018) and more recently in Zebrafish (Nguyen et al, 2017).
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