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Review
. 2009:25:197-220.
doi: 10.1146/annurev.cellbio.24.110707.175242.

Mechanisms of growth and homeostasis in the Drosophila wing

Ricardo M Neto-Silva  1 , Brent S Wells, Laura A Johnston
Affiliations
Review

Mechanisms of growth and homeostasis in the Drosophila wing

Ricardo M Neto-Silva et al. Annu Rev Cell Dev Biol. 2009.

Abstract

Animal shape and size is controlled with amazing precision during development. External factors such as nutrient availability and crowding can alter overall animal size, but individual body parts scale reproducibly to match the body even with challenges from a changing environment. How is such precision achieved? Here, we review selected research from the last few years in Drosophila--arguably the premier genetic model for the study of animal growth--that sheds light on how body and tissue size are regulated by forces intrinsic to individual organs. We focus on two topics currently under intense study: the influence of pattern regulators on organ and tissue growth and the role of local competitive interactions between cells in tissue homeostasis and final size.

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Figures

Figure 1
Figure 1. The development of Drosophila imaginal discs
Larval development begins at 24 hours after egg laying (AEL). Top panels, larvae from each of the three instars are shown above. Larval instars are designated by L1, L2, and L3 and the approximate time of molting is noted. Puparium formation (PF) begins at approximately 120 hours AEL (in animals raised at 25°C). L3 larvae are noted by dotted box. Bottom panels, L3 wing discs dissected from L3 larvae at the times indicated below. The wing disc grows rapidly and increases its size through cell proliferation, and patterning of cell fates occurs simultaneously. At wandering stage the growth of the wing disc slows, and the larva forms a puparium in response to hormones. The final size of the wing is largely determined by the time the animal enters pupal development.
Figure 2
Figure 2. Cell proliferation and patterning in the wing disc
A) Wingless (Wg; red) is expressed a stripe of cells at the dorsal (D)-ventral (V) boundary of the wing disc. Wg is secreted and forms a gradient across the disc. In addition to expression along the boundary, Wg is expressed in two concentric rings, the inner ring (IR) and outer ring (OR). The IR separates the distal cells (within the IR), which will form the wing blade, from the proximal cells that will form the hinge, pleura and thorax of the fly B) Dpp (green) is expressed in a stripe of anterior of cells next to the anterior (A)-posterior (P) boundary of the disc, which is established in the embryo. Dpp is also secreted and diffuses across the disc in a graded manner (not evident in this image) C) Brinker (Brk), a transcriptional repressor of Dpp target genes, is expressed in a gradient that is complementary to Dpp. See text for more information D) Vestigial (Vg), the wing selector gene, is activated in most cells of the wing pouch (the presumptive wing blade). Vg expression is transcriptionally controlled through enhancers that integrate information from Notch, Wg, and Dpp E) Expression of Vg at the D-V boundary is controlled by the “Boundary Enhancer” (VgBE). This enhancer is regulated by Notch activity and is activated midway through L2 F) In most distal cells of the wing disc Vg is regulated through the “Quadrant Enhancer” (VgQE), which is regulated by both Wg and Dpp, and also requires input from Vg itself (see text for details) G) BrdU is incorporated into cells in S phase of the cell cycle, and appears uniform across the proliferating wing disc from L1 through most of L3. Late in L3, cells along the D-V boundary exit the cell cycle as part of a proneural program and do not incorporate BrdU (shown as a stripe of black across the middle of the disc) H) Mitotic cells, marked by an antibody that recognizes a mitosis-specific phosphorylation of Histone 3, show a distribution similar to cells in S phase (G) I) Cells undergoing apoptosis are labeled by TUNEL assay. Cell death in the wing disc is minimal and non-patterned during most of larval development.
Figure 3
Figure 3. A model for regulation of wing growth by Dpp, Fat, and Hpo/Wts
(A) Dpp is secreted from a stripe of cells along the anterior edge of the A-P boundary and moves across the disc to form a gradient of signaling activity (shown in green) (B) The gradient of Dpp signaling activity influences the expression of Fat regulators, Ds and Fj (not shown). Ds (orange bars) modulates Fat signaling by polarizing its distribution (as shown, blue bars) or its activity within a cell. This polarization would allow for differences in Fat activity within the cell. Yki is retained in the cytoplasm by high Fat and Wts activity, but allowed to enter the nucleus where there are fewer Ds-Fat complexes (C) Polarized Fat activity locally inactivates Dachs (D), and thereby increases the stability and activity of Wts, which phosphorylates Yki and causes its retention in the cytoplasm by 14-3-3-proteins (left side of cell). Wts activity is also regulated by Hpo, which can integrate inputs relayed by Ex (itself regulated by Fat) and Mer (regulated by an unknown receptor). A local reduction in Ds-Fat complexes allows D to accumulate, causing degradation of Wts (right side of cell). A regional pool of unphosphorylated Yki is thus produced, which translocates to the nucleus; together with Sd, Yki promotes the expression of downstream target genes such as cycE, diap1 and bantam.
Figure 4
Figure 4. Expansion of the wing blade primordium by a Vestigial feed-forward circuit
(A) Shortly after specification in early L2 the wing primordium is subdivided into Dorsal and Ventral compartments. Short-range Delta/Serrate-Notch signaling across the D-V boundary induces cells straddling the boundary to express Wg and Vg, the latter driven by the Vg Boundary Enhancer (BE) (B) By early third instar, D-V border cells send a Vg-dependent signal (X) that is required, together with Wg, to activate the Vg quadrant enhancer (QE) in adjacent cells, thereby upregulating Vg expression. Reiterative cycles of this short-range feed-forward signaling system expands the population of Vg-expressing cells in the presumptive wing blade (C) In response to both Wg (red) and Dpp (green) the QE mediates the feed-forward Vg auto-regulation and allows expansion of the wing primordium. Besides contributing to Vg autoregulation, Dpp stimulates proliferation of presumptive wing pouch cells through its effects on Hpo/Wts signaling (Figure 3), thereby sustaining the cell population from which wing cells can be recruited.
Figure 5
Figure 5. Tissue homeostasis through cell competition
A) Interactions between neighboring cells in a growing epithelium allow mutual assessment of metabolic state. If no metabolic difference is detected between neighboring cells, all cells survive and reproduce to populate the tissue. Detection of a metabolic difference between neighboring cells leads to competition: the relatively more robust state of ‘winner’ cells (blue) gives them a growth advantage, but signals exchanged between the populations lead to death of their relatively less robust neighbors (‘loser’ cells, orange) B) A model of cell competition. We postulate that cells continually monitor their own metabolic state (effectively a measure of ribosome function) and that of their neighbors. This mutual sensing may be through the production of soluble factors by both cells that report ribosome function. Cells with lower levels of dMyc or Rp have reduced ribosome function (“losers”) and are sensed by neighbor cells with higher dMyc or Rp levels and thus higher ribosome function (“winners”). Winner cells relay a death signal to loser cells, which respond by activating the JNK stress pathway, induce expression of the proapoptotic factor Hid, and commit suicide. Winner cells are protected from these death signals by an unknown mechanism. Winner cells are stimulated to proliferate more in response to signals produced by dying loser cells (green arrow). The extracellular factors produced during cell competition can diffuse across the epithelium and modulate growth and cell survival decisions up to 10 cell diameters from the competitive boundary (A). Although JNK activity is induced in loser cells, it is not required for their death.
Figure 6
Figure 6. Bilateral symmetry of wing size requires Hid-induced cell death
Mutations that remove Hid function (in this case using a hid null mutation over a small deletion (H99) that removes hid and two other pro-apoptotic genes) leads to bilateral asymmetry of wing size. Loss of Hid-induced death, which causes >90% of cell competition-induced apoptosis, subtly but significantly alters wing growth and causes fluctuating asymmetry, an indicator of developmental instability A) Left and right wings from an individual fly that is null for the hid gene B) The frequency of asymmetry of left and right wings increases significantly in animals that lack hid. Graph plots the mean length difference (in pixels) between left (L) and right (R) wing sizes from 8 hid/+ and 12 hid/H99 individual female flies. L and R wing size are matched in more than 60% of hid/+ animals. In contrast, in the complete absence of Hid (hid/H99) L and R wings are frequently mis-matched in size.
Figure 7
Figure 7. Morphogenetic Apoptosis
A) Morphogenetic apoptosis eliminates cells that disrupt the continuity of a morphogen gradient. Left, an uninterrupted Dpp gradient. Right, the field of cells along this gradient B) One cell within the gradient acquires a mutation (*) that disrupts the continuity of the gradient C) Proliferation of the mutated cell widens the discontinuity. The discrepancy in graded morphogen expression activates the JNK stress pathway in the mutant cells and in adjacent wildtype cells, resulting in cell death and clearance from the epithelium. This process does not occur in the absence of JNK activity D) Neighboring wildtype cells proliferate, reconstituting a continuous gradient.
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