Model of compensatory proliferation in response to apoptosis. In multi-cellular organisms, morphogenesis is composed of patterned cell proliferation followed by cell differentiation (green). Compensatory proliferation can be induced in response to cell loss to maintain tissue homeostasis. If execution of cell death is blocked, for example by expression of P35, an effector-caspase inhibitor in Drosophila, ‘undead cells’ (red) continue to secrete signals to induce proliferation, resulting in tissue overgrowth.

Two modes of apoptosis-induced compensatory proliferation in proliferating and differentiating eye tissues in Drosophila. (a) Schematic outline of the late-third instar eye imaginal disc. Anterior is to the left. The developing larval eye disc is composed of the anterior proliferating tissue (red) and the posterior differentiating tissue (green), which are separated by G1-arrested cells, the morphogenetic furrow (MF) and the second mitotic wave (SMW). The eyeless (ey) promoter is expressed in the anterior part (red); the GMR promoter is expressed in the posterior part (green) and in the SMW. (b) An eye imaginal disc from a 3rd instar wild-type larva labeled with BrdU as the proliferation marker. The anterior half of the disc [red in (a)] is heavily proliferating. Posterior to the SMW [green in (a)], proliferation has stopped and cells are differentiating into photoreceptor neurons and accessory cell types. The SMW is marked by a white arrowhead. (c) Co-expression of hid and P35 under ey control (ey-Gal4, UAS-hid, UAS-P35) triggers overgrowth of the anterior compartment [red in (a); compare with (b)]. The white bar indicates the extent of overgrowth [compare to (b)]. (d) Expression of hid under GMR control (GMR-hid) triggers compensatory proliferation (white arrow) posterior to the SMW [green in (a); compare with (b)]. Part (a) adapted, with permission, from Ref. [13].

The apoptotic pathway in Drosophila. In response to apoptotic stimuli, expression of the pro-apoptotic genes hid, reaper and grim releases the initiator caspase Dronc from inhibition by Diap1. Free Dronc then associates with the adaptor protein Ark and proteolytically processes the effector caspases DrICE and Dcp-1 to induce apoptosis.

Models of distinct mechanisms of compensatory proliferation in proliferating versus differentiating tissues in Drosophila. (a,b) Molecular mechanisms of apoptosis-induced compensatory proliferation in proliferating tissues (a) and differentiating tissues (b). An apoptotic cell (left) and a cell that is induced to undergo compensatory proliferation (right) are shown. Dashed arrows indicate unknown interactions. The scaffolding protein Ark is omitted for clarity (Figure 2). (c) Schematic outline of various cell types in the differentiating eye tissue. Hh produced in apical dying photoreceptor neurons (numbered colored cells) non-autonomously induces cell-cycle re-entry of basally-located unspecified cells (gray cells). ‘Apical’ and ‘basal’ refer to the apical and basal sides of the disc. The SMW is omitted for clarity. Part (c) adapted, with permission, from Ref. [13].