Sizing it up: the mechanical feedback hypothesis of organ growth regulation

Abstract

The question of how the physical dimensions of animal organs are specified has long fascinated both experimentalists and computational scientists working in the field of developmental biology. Research over the last few decades has identified many of the genes and signaling pathways involved in organizing the emergent multi-scale features of growth and homeostasis. However, an integrated model of organ growth regulation is still unrealized due to the numerous feedback control loops found within and between intercellular signaling pathways as well as a lack of understanding of the exact role of mechanotransduction. Here, we review several computational and experimental studies that have investigated the mechanical feedback hypothesis of organ growth control, which postulates that mechanical forces are important for regulating the termination of growth and hence the final physical dimensions of organs. In particular, we highlight selected computational studies that have focused on the regulation of growth of the Drosophila wing imaginal disc. In many ways, these computational and theoretical approaches continue to guide experimental inquiry. We demonstrate using several examples how future progress in dissecting the crosstalk between the genetic and biophysical mechanisms controlling organ growth might depend on the close coupling between computational and experimental approaches, as well as comparison of growth control mechanisms in other systems.

Keywords: Computational and mathematical modeling; Drosophila wing disc; Intercellular signaling; Limb development; Mechanobiology.

Figure 1:

(A-B). The wing imaginal disc as a model system for studying organ growth control. The wing discs are epithelial sacs loosely attached to the tracheal system during larval growth (A). During the third instar larvae (shown in B) the wing disc assumes a folded morphology with the pouch cells prominently forming an ellipse shape in the center of the “pear”-shaped organ (B’ and B”). Red marks the nubbin expression domain (nubbin-mcherry) and green marks dad expression (dad-GFP), which a target and inhibitor of DPP signaling. The transgenic fly line was a gift from the Affolter lab. During metamorphosis, the pouch will undergo eversion and elongation to form the adult wing. The pouch is patterned by morphogen gradients that establish a Cartesian coordinate system along the anterior-posterior (AP) and dorsal-ventral (DV) axes. The Dachsous-Fat pathway forms a gradient along the proximal – distal axis. C: Hyperplastic mutants such as wts^P2 do not terminate growth and become highly folded. D: Proliferation depends on the milieu as shown

Figure 2:

Graphical representation of selected works exploring the mechanical feedback hypothesis in wing discs. Inset figures are adapted from [,,,,–92]. Used with permission.