The Systemic Control of Growth

Abstract

Growth is a complex process that is intimately linked to the developmental program to form adults with proper size and proportions. Genetics is an important determinant of growth, as exemplified by the role of local diffusible molecules setting up organ proportions. In addition, organisms use adaptive responses allowing modulating the size of individuals according to environmental cues, for example, nutrition. Here, we describe some of the physiological principles participating in the determination of final individual size.

Figure 1.

Environmental and developmental signals controlling steroid hormone production and the developmental timing. Developmental transitions are controlled by peaks of the steroid hormone ecdysone. Ecdysone is produced by the prothoracic gland (PG), an endocrine tissue that integrates various signals to adjust the progression through the life cycle with developmental and environmental cues. In late larval development, a sharp increase in the production of prothoracicotropic hormone (PTTH) by two pairs of brain neurons induces the production of ecdysone by the PG. Secreted factors produced by growing or regenerating tissues inhibit the larval/pupal transition, allowing coupling tissue size assessment with the developmental program. Information on body size could also come from the levels of circulating oxygen. Finally, insulin and target of rapamycin complex 1 (TORC1) signaling in the PG coordinate steroid hormone production with nutritional conditions. IPCs, insulin-producing cells; Dilp, Drosophila insulin-like peptide; InR, insulin receptor; PDF, pigment dispersing factor; DHR-3/4, Drosophila hormone receptor 3/4; ERK, extracellular signal-regulated kinase.

Figure 2.

Local and systemic modulations of insulin signaling. The tight control of insulin signaling relies on complex mechanisms of interorgan communication. The insulin-producing cells (IPCs) produce Drosophila insulin-like peptide (Dilp)2, 3, and 5, which represent the main systemic source of circulating insulin during the growth phases (larval stages). Several inputs affect dilp gene expression in the IPCs, whereas nutritional information is sensed by the fat body and relayed by humoral factors controlling Dilp secretion. Dilp6 is induced upon nutrient shortage by fat cells to sustain growth of high priority organs. Several Dilp-binding factors modulate the activity of circulating Dilps (SDR, dALS, and Imp-L2). An interplay between glial and neural cells promotes growth and proliferation of larval neuroblasts and allows them to evade nutrient control during late larval development. NBs, neuroblasts; PG, prothoracic gland; AAs, amino acids; Hh, Hedgehog; FOXO, Forkhead box-O transcription factor; PI3K, phosphoinositide-3-kinase; Upd2, unpaired 2; Imp-L2, imaginal morphogenesis protein-Late 2; dALS, Drosophila acid labile subunit; Alk, anaplastic lymphoma kinase; SDR, secreted decoy of InR; Jeb, Jelly belly.

Figure 3.

The cross talk between insulin and ecdysone in body growth control. Insulin signaling promotes tissue growth and enhances ecdysone production in the prothoracic gland (PG). Besides its well-described function in developmental transitions, ecdysone has a dual effect on tissue growth. Although it activates autonomous growth of larval tissues through a still unknown mechanism, it inhibits systemic growth by down-regulating dMyc expression in the fat body, resulting in a general inhibition of insulin signaling. The humoral signal produced by fat cells on dMyc activation remains unknown. Ecdysone autonomously antagonizes insulin signaling in fat cells by repressing the growth-promoting microRNA (miRNA) miR-8, whose function is conserved in mammals. miR-8 and its target u-shaped (ush) could also affect systemic growth through another mechanism (dashed line). Finally, the activation of Dilp6 by ecdysone signaling in fat cells could promote specific tissue growth during metamorphosis.