Feedback control of organ size precision is mediated by BMP2-regulated apoptosis in the Drosophila eye

Abstract

Biological processes are intrinsically noisy, and yet, the result of development—like the species-specific size and shape of organs—is usually remarkably precise. This precision suggests the existence of mechanisms of feedback control that ensure that deviations from a target size are minimized. Still, we have very limited understanding of how these mechanisms operate. Here, we investigate the problem of organ size precision using the Drosophila eye. The size of the adult eye depends on the rates at which eye progenitor cells grow and differentiate. We first find that the progenitor net growth rate results from the balance between their proliferation and apoptosis, with this latter contributing to determining both final eye size and its variability. In turn, apoptosis of progenitor cells is hampered by Dpp, a BMP2/4 signaling molecule transiently produced by early differentiating retinal cells. Our genetic and computational experiments show how the status of retinal differentiation is communicated to progenitors through the differentiation-dependent production of Dpp, which, by adjusting the rate of apoptosis, exerts a feedback control over the net growth of progenitors to reduce final eye size variability.

Looking across the gap: Understanding the evolution of eyes and vision among insects

“…Drosophila eyes develop from a pair of internalized eye-antennal imaginal discs that grow through the first two larval instars before differentiating during the third instar and then fusing during metamorphosis in the pupal stage [28][29][30] (Box 2). Although this process was already well-understood, [28,31] Navarro et al (2024) [32] recently provided important new insights into how cell division, differentiation, and cell death are coordinated in the developing eye disc of Drosophila to specify cell number and eye size.…”

Size precision in insect eyes

“…Cell death is involved in the removal of excess cells in the differentiating side of the eye primordium [ 6 ]. Using a sensitive antibody to detect apoptotic cells in the developing eye primordium, Casares, Ares, and colleagues detected the presence of apoptotic cells also in the progenitor cell population and present evidence that these cells are distributed in a stripe abutting the differentiation wave ([ 5 ], Fig 1 ). When apoptosis was blocked in this stripe by targeted expression of a transgene carrying synthetic miRNAs against the pro-apoptotic genes hid , reaper , and grim , the resulting eyes became significantly larger.…”

“…The impact of Dpp receptor depletion on eye size and size variability was rescued upon intracellular derepression of the Dpp pathway or apoptosis blockage. In flies carrying the Bar mutation, dpp expression in newly differentiating retinal cells is partially compromised [ 7 ] and the resulting adult eyes are smaller, more variable in size, and highly asymmetric [ 5 ]. Intracellular derepression of the Dpp pathway or apoptosis blockage rescued eye size, variability, and asymmetry in Bar mutant flies.…”

“…The exquisite regulation of organ size in this animal is exemplified by the reduced variability observed between the left and right wings of the same insect (fluctuating asymmetry, FA [1][2][3][4]). A new study unravels an organ-intrinsic mechanism of growth control in the developing fly eye that confers size precision through feedback interactions between proliferating and differentiating cells [5]. This mechanism reduces eye size variability between and within animals, thus contributing to the symmetry between contralateral eyes and having a clear potential impact on eye functionality.…”