This Title All WIREs
How to cite this WIREs title:
WIREs Dev Biol
Impact Factor: 3.883

Size control: the developmental physiology of body and organ size regulation

Full article on Wiley Online Library:   HTML PDF

Can't access this content? Tell your librarian.

The developmental regulation of final body and organ size is fundamental to generating a functional and correctly proportioned adult. Research over the last two decades has identified a long list of genes and signaling pathways that, when perturbed, influence final body size. However, body and organ size are ultimately a characteristic of the whole organism, and how these myriad genes and pathways function within a physiological context to control size remains largely unknown. In this review, we first describe the major size‐regulatory signaling pathways: the Insulin/IGF‐, RAS/RAF/MAPK‐, TOR‐, Hippo‐, and JNK‐signaling pathways. We then explore what is known of how these pathways regulate five major aspects of size regulation: growth rate, growth duration, target size, negative growth and growth coordination. While this review is by no means exhaustive, our goal is to provide a conceptual framework for integrating the mechanisms of size control at a molecular‐genetic level with the mechanisms of size control at a physiological level. WIREs Dev Biol 2015, 4:335–356. doi: 10.1002/wdev.181 This article is categorized under: Establishment of Spatial and Temporal Patterns > Regulation of Size, Proportion, and Timing Signaling Pathways > Global Signaling Mechanisms
Size‐regulatory signaling pathways. (a) The insulin/IGF1‐signaling (IIS) pathway. (b) The RAS/RAF/MAPK‐signaling pathway. (c) The TOR‐signaling pathway. (d) The Hippo‐signaling pathway. (e) The JNK‐signaling pathway. Transcribed growth factors targeted by MAPK, Hippo, and JNK‐signaling pathways include secreted factors, protein synthesis and cell‐cycle regulators and anti‐apoptotic factors. Note that any individual growth factor may be regulated by only one pathway. IGF1R: insulin‐growth factor 1 receptor; Pi3K: phosphatidylinositol‐4,5‐bisphosphate 3‐kinase; IRS: IGF1R substrate; PIP2/3: phosphatidylinositol bi/triphosphate; GSK3: glycogen synthase kinase 3; FOXO1: forkhead transcription factor 1; SHC: Src homology 2 domain containing protein; Grb2: growth factor receptor‐bound protein 2; SOS: son‐of‐sevenless; MEK: mitogen/extracellular signal‐regulated kinase; MAPK: mitogen‐activated protein kinase; TSC1/2: tuberous sclerosis proteins 1/2; Rheb: Ras homolog enriched in brain; AMPK: 5′ adenosine monophosphate‐activated protein kinase; TOR: target of rapamycin; mLST8: mammalian Lethal with SEC13 protein 8; S6K: ribosomal protein S6 kinase β‐1; Crb: crumb; Mer: merlin; Ex: expanded; Sav1: salvador; Mats: Mob as tumor suppressor; Yki: Yorkie; Sd: scalloped; TNFR: tumor necrosis factor receptor; GPCR: G protein‐coupled receptors; RTK: receptor tyrosine kinase; MAPKKK: MAPK kinase kinase; MKK4/7: dual specificity mitogen‐activated protein kinase kinase 4/7; JIP: JNK‐interacting protein; TF: transcription factor.
[ Normal View | Magnified View ]
Models of target size regulation in Drosophila wing imaginal disks. (a) Under the morphogen gradient model disk growth is maintained while a morphogen gradient is maintained. At a cellular level, there is evidence that the Dpp gradient generates opposing gradients of Fj and Ds. This in turn may lead to the asymmetrical activation of Fat, which frees Dachs to inhibit Warts, de‐repressing Yki and promoting cell growth and proliferation. (a′) When the gradient becomes sufficiently flat at target size, symmetrical activation of Fat inhibits Warts, allowing Warts to deactivate Yki and suppress cell growth and proliferation. (b) Under the Shraiman model, growth in the center and the periphery of the disk is driven by the morphogen gradient, as in (a). (b′) Growth stops when cells at the periphery of the disk grows beyond the morphogen gradient, inhibiting their proliferation and imposing a compressive force on the cells at the center of the disk (grey arrows), stopping their growth also. (c) Under the Aegerter‐Wilmsen model, growth in the center of the disk is driven by the morphogen gradient while growth at the periphery is driven by the stretch imposed by cell proliferation at the center of the disk (black arrows). (c′) Growth stops when compression at the center of the disk imposed by the peripheral cells overcomes the growth‐promoting effects of the morphogen gradient, which in turn eliminates stretch at the periphery of the disk, stopping cell growth and proliferation there also.
[ Normal View | Magnified View ]
The physiological mechanisms that regulate the duration of growth in Drosophila. (a) The synthesis of ecdysone by the prothoracic gland is positively regulated by several signaling pathways, including the insulin/IGF1‐signaling (IIS) pathway, the RAS/RAF/MAPK‐signaling pathway (blue arrow) and the TOR‐signaling pathway (green arrow). Ecdysteroidogenesis is also negatively regulated by dILP8, through an unknown mechanism, and autoregulated by ecdysone via dynamic positive and negative feedback loops (red arrows). (b) Developmental transition is driven by peaks of ecdysone. These transitions include larval molts, attainment of critical size, the cessation of feeding (and growth) and pupariation. IIS and RAS/RAF/MAPK‐signaling regulates the timing of the critical size ecdysone peak, while TOR‐signaling regulates the terminal growth period between the critical size peak and the ecdysone peak that stops feeding. (c) Final body size is therefore regulated by the size of the larva at critical size plus the amount of growth achieved during the TGP.
[ Normal View | Magnified View ]

Browse by Topic

Signaling Pathways > Global Signaling Mechanisms
Establishment of Spatial and Temporal Patterns > Regulation of Size, Proportion, and Timing