Abstract
Most cells in a developing organ stop proliferating when the organ reaches a correct, final size. The underlying molecular mechanisms are not understood. We find that in Drosophila the hormone ecdysone controls wing disc size. To study how ecdysone affects wing size, we inhibit endogenous ecdysone synthesis and feed larvae exogenous ecdysone in a dose-controlled manner. For any given ecdysone dose, discs stop proliferating at a particular size, with higher doses enabling discs to reach larger sizes. Termination of proliferation coincides with a drop in TORC1, but not Dpp or Yki signaling. Reactivating TORC1 bypasses the termination of proliferation, indicating that TORC1 is a main downstream effector causing proliferation termination at the maximal ecdysone-dependent size. Experimental manipulation of Dpp or Yki signaling can bypass proliferation termination in hinge and notum regions, but not the pouch, suggesting that the mechanisms regulating proliferation termination may be distinct in different disc regions.
Highlights
Most cells in a developing organ stop proliferating when the organ reaches a correct, final size
To study the effect of ecdysone signaling on wing disc proliferation in a controlled manner, we aimed to abolish the endogenous synthesis of ecdysone and to replace it with exogenously fed ecdysone at fixed levels
Since we previously showed that the cell cycle promotes TORC1 via CycD/Cdk[4] in the wing disc[42], we tested the option that TORC1 is downstream of a cell cycle block by overexpressing CycD/Cdk[4], this did not cause cells to continue proliferating (Supplementary Fig. 8d)
Summary
Most cells in a developing organ stop proliferating when the organ reaches a correct, final size. A mechanistic model where cells measure time has been excluded by slowing down disc growth using ‘Minute’ mutations, and seeing that discs compensate by extending developmental time, thereby achieving a normal size[16,17] These experiments have revealed that size sensing occurs at the level of compartments in the wing (e.g., the posterior versus anterior compartments)[17], and that this occurs prior to pupation[17]. High levels of ecdysone which occur at the onset of metamorphosis cause differentiation of wing disc cells and their arrest in G210,18 This peak of ecdysone leads to termination of growth and proliferation in the wing. Unclear is whether ecdysone plays a permissive function in allowing wing cells to proliferate, or whether ecdysone levels control final wing disc size
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