Regulation of organ growth by morphogen gradients

Abstract

Morphogen gradients play a fundamental role in organ patterning and organ growth. Unlike their role in patterning, their function in regulating the growth and the size of organs is poorly understood. How and why do morphogen gradients exert their mitogenic effects to generate uniform proliferation in developing organs, and by what means can morphogens impinge on the final size of organs? The decapentaplegic (Dpp) gradient in the Drosophila wing imaginal disc has emerged as a suitable and established system to study organ growth. Here, we review models and recent findings that attempt to address how the Dpp morphogen contributes to uniform proliferation of cells, and how it may regulate the final size of wing discs.

Figure 1.

Uniform growth together with scaled morphogen gradients allows determination of cell fates at different time points without losing the right proportions. (A) The case in which growth is uniform, but the morphogen gradient is not scaled. This leads to a change in the proportions of target gene expression domains. Thus, in this situation, the final proportions strictly depend on the precise time-point of cell fate determination. (B) A morphogen gradient scaled to organ size, but driving nonuniform growth. The expression domains of target genes are in proportion only until cell fate determination. Thus, also here, the time point of cell fate determination cannot be shifted without a change in the final proportions. (C) A morphogen gradient scaled to organ size together with uniform growth. In this situation, the expression domains of target genes keep the right proportions independent of the time-point of cell fate determination. Note that the values of the proportions are not based on experimental data. (P1 and P2) Threshold levels for target gene 1 and 2, (E) endpoint of the organ.

Figure 2.

The Dpp gradient in the developing wing imaginal disc of Drosophila serves as a model to study organ patterning and growth. (A) Expression domains of dpp, brk, sal, and omb. (B) Dpp is secreted from its site of production in the center of the disc and spreads into the A and P compartment, establishing a gradient with highest levels in the center and lowest in the periphery. brk transcription is gradually repressed by Dpp signaling activity, leading to a brk gradient inverse to the Dpp gradient. Brk levels are important to set the expression boundaries of sal and omb. omb is repressed by high levels of Brk, and sal by lower levels. Consequently, omb is expressed in a broader domain than sal. (A) Anterior compartment, (P) posterior compartment.

Figure 3.

Models addressing how the Dpp gradient can account for uniform growth within the wing disc. (A) Cells are primed for different sensitivity to the mitogenic activity of Dpp, which leads to uniform proliferation during the growth period. (B) Dpp drives proliferation at constant levels above the threshold value, which is reached within the entire wing disc. (C) In the gradient model, the slope of the Dpp gradient drives proliferation. (D) A modified version of the gradient model, in which the disc is subdivided into two regions, the medial and the lateral regions. In the medial region, where the Dpp gradient is sufficiently steep, cells proliferate in response to the gradient, and in the lateral region, where the gradient becomes very shallow, cells proliferate in response to absolute Dpp levels. (E) A growth inhibitor in parallel to Dpp evens out high differences of Dpp signaling along the AP axis. (F) In this model, lateral cells have a growth advantage compared with medial cells, and the Dpp/Brk system is needed to curb lateral proliferation. If absent, lateral overproliferation by an unknown mechanism inhibits growth in the medial area.

Figure 4.

Models for final size control of the wing disc by the Dpp gradient. (A) This model is based on the assumption that Dpp levels in the center and the periphery are fixed, resulting in a decline of the slope of the Dpp gradient when the disc grows. Growth stops when the slope is sufficiently shallow. (B1) This model assumes that the Dpp gradient does not adapt to the disc size. Once the disc has grown, lateral cells do not receive sufficient Dpp and stop proliferating. A mechanical feedback mechanism exerts a compression force to medial cells, leading to a growth stop also in this region. (B2) Growth of the wing disc is governed by a combination of morphogens, which are concentrated at the center of the disc, and stretching and compression forces. High growth factor levels in the center of the disc lead to local growth. This causes stretching, and thus growth in the circumferential regions of the disc, with some stretching still remaining. Stretching forces in the periphery in turn lead to compression of medial cells, which influences growth negatively. As the disc grows, the stretched region becomes wider and compression in the center of the disc becomes stronger. Growth stops once the influence of compression forces becomes bigger than the growth promoting influence by Dpp. (C) In parallel to a growth activator, a growth inhibitor is expressed. Initially, the growth activator is expressed at higher levels. Over time, this ratio changes, and growth stops when the inhibitor reaches a concentration higher than the activator.