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Regulation of Body Size and Growth Control

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Regulation of Body Size and Growth Control | FLYBOOK DEVELOPMENT AND GROWTH Regulation of Body Size and Growth Control Michael J. Texada, Takashi Koyama, and Kim Rewitz1 Department of Biology, University of Copenhagen, 2100, Denmark ORCID IDs: 0000-0003-2551-3059 (M.J.T.); 0000-0003-4203-114X (T.K.); 0000-0002-4409-9941 (K.R.) ABSTRACT The control of body and organ growth is essential for the development of adults with proper size and proportions, which is important for survival and reproduction. In animals, adult body size is determined by the rate and duration of juvenile growth, which are influenced by the environment. In nutrient-scarce environments in which more time is needed for growth, the juvenile growth period can be extended by delaying maturation, whereas juvenile development is rapidly completed in nutrient-rich conditions. This flexibility requires the integration of environmental cues with developmental signals that govern internal checkpoints to ensure that maturation does not begin until sufficient tissue growth has occurred to reach a proper adult size. The Target of Rapamycin (TOR) pathway is the primary cell-autonomous nutrient sensor, while circulating hormones such as steroids and insulin-like growth factors are the main systemic regulators of growth and maturation in animals. We discuss recent findings in Drosophila melanogaster showing that cell-autonomous environment and growth-sensing mechanisms, involving TOR and other growth-regulatory pathways, that converge on insulin and steroid relay centers are responsible for adjusting systemic growth, and development, in response to external and internal conditions. In addition to this, proper organ growth is also monitored and coordinated with whole-body growth and the timing of maturation through modulation of steroid signaling. This coordination involves interorgan communication mediated by Drosophila insulin-like peptide 8 in response to tissue growth status. Together, these multiple nutritional and developmental cues feed into neuroendocrine hubs controlling insulin and steroid signaling, serving as checkpoints at which developmental progression toward maturation can be delayed. This review focuses on these mechanisms by which external and internal conditions can modulate developmental growth and ensure proper adult body size, and highlights the conserved architecture of this system, which has made Drosophila a prime model for understanding the coordination of growth and maturation in animals. KEYWORDS checkpoint; critical weight; DILP8; Drosophila; ecdysone; insulin; metamorphosis; prothoracic gland; PTTH; timing; FlyBook TABLE OF CONTENTS Abstract 269 Introduction 270 Regulation of Cell Size and Number 271 The intracellular TOR pathway 272 The hormone-sensitive fork: the tuberous sclerosis complex proteins and Rheb 272 The nutrient-sensitive fork: the Rag GTPases 274 The effects of TOR activity 275 The proto-oncogenic transcription factor Myc 275 Continued Copyright © 2020 by the Genetics Society of America doi: https://doi.org/10.1534/genetics.120.303095 Manuscript received April 29, 2020; accepted for publication June 29, 2020. Available freely online through the author-supported open access option. 1Corresponding author: Department of Biology, University of Copenhagen, Universitetsparken 15, Bldg. 3.3.430, 2100 Copenhagen, Denmark. E-mail: Kim.Rewitz@ bio.ku.dk Genetics, Vol. 216, 269–313 October 2020 269 CONTENTS, continued The Hippo local signaling system 276 Local growth-factor signaling 276 The intracellular insulin-signaling pathway 277 Intracellular signaling downstream of ecdysone 277 Body-Size Control 278 Duration and rate of growth 278 The insulin system: coupling of growth to nutritional and environmental inputs 278 Control of systemic growth through DILP signaling 281 Regulation of IPC activity and functional role of DILPs 282 DILP expression 282 DILP release 283 Modulation of circulating DILP activity 284 Glial and neuronal relays controlling DILP signaling 284 Peripheral organs relaying nutrient and oxygen status to the IPCs 286 The ecdysone signaling system: coordinating growth and developmental maturation 287 Control of prothoracicotropic hormone release 288 Integration of signals within the PG 289 Developmental cues and size-sensing in the PG 289 Other signals regulating ecdysone production 291 Interactions between ecdysone and insulin signaling 292 Developmental and nutritional checkpoints 293 CW 293 Assessment of CW 294 Disc checkpoint 295 Coupling developmental timing to imaginal disc growth 296 Allometry and scaling of organ growth and body size 297 Concluding Remarks 297 HE nature of the mechanisms by which animals control transition to adulthood comparable with mammalian puberty Tthe growth of their bodies and their different parts to (Figure 1) (Yamanaka et al. 2013a; Boulan et al. 2015; produce adults of correct size and proportions is a fundamen- Juarez-Carreño et al. 2018). In Drosophila, nutritional status tal question. Studies in Drosophila have provided insight into is linked to a checkpoint called critical weight (CW) that these questions through the identification of systems that link occurs early in the final larval instar, which is important for body and organ growth to environmental and developmental determining final body size (Mirth and Riddiford 2007). In- cues. This research illustrates how organs exchange external- sulin regulates CW and is the primary hormone mediating and internal-status information via circulating hormones, and systemic growth control in response to nutrient sensing, how this information is integrated by the neuroendocrine cir- while cellular nutrient sensing is mediated by the Target of cuitry regulating insulin-like growth factor and steroid hormone Rapamycin (TOR) pathway. The main nutrient-sensing tissue signaling, the two main factors that underlie developmental is the fat body,which receives information from cellular levels growth regulation and coordination. of amino acids through TOR as well as other environmental In many animals, growth is largely restricted to the juvenile conditions including oxygen levels (Colombani et al. 2003; stage, and adult body size is therefore determined by the size Texada et al. 2019a). In response to these cues, the fat body at which the juvenile undergoes maturation (Tennessen and secretes adipokines that mediate systemic growth responses Thummel 2011). Intrinsic developmental programs that de- through their regulatory effects on insulin signaling (Rajan termine species-specific size are modulated by environmental and Perrimon 2012; Sano et al. 2015; Agrawal et al. 2016; cues to produce adults with proper size and proportions in Delanoue et al. 2016; Koyama and Mirth 2016; Texada et al. changing environments. These environmental factors affect 2019a). the rate of growth as well as the timing of maturation, which The steroid ecdysone is the key factor regulating develop- ends the juvenile growth period. In Drosophila, almost all mental transitions in Drosophila. Pulses of ecdysone control growth occurs in the larval stage, which is terminated by molting and metamorphosis (Figure 1), while between pupariation, which marks the onset of metamorphosis, the pulses, the lower, basal level of ecdysone negatively regulates 270 M. J. Texada et al. Figure 1 The development of D. melanogaster.A fertilized Drosophila embryo spends roughly 1 day developing into a mobile, feeding larva (under nor- mal conditions). After hatching, the larva feeds for the next 4 days, growing to 200 times its initial size; to accommodate this dramatic growth, the larva sheds its cuticle twice during this time in molts that separate the first, second, and third larval “instars.” After larval growth is complete, the animal wanders away from its food source to find a location suitable for the 4-day metamorphosis period, during which time the animal survives on stored material while its larval tissues are degraded and adult structures fin- ish their development. The adult emerges (“eclo- ses”) once this process is complete. Pulses of the insect steroid hormone ecdysone regulate the ani- mal’s progression through these developmental stages. the growth of larval tissues by antagonizing insulin signaling transitions, are discussed further below. These systemic factors (Colombani et al. 2005; Yamanaka et al. 2013a; Moeller et al. act through their effects within individual cells, where the 2017). Thus, the interaction between insulin and ecdysone information they convey is integrated with intracellular path- controls final body size. In addition to the nutritional check- ways that reflect each cell’s tissue context and its internal met- point at CW, the larval growth period is determined by a abolic state. Through the combined effects of these layers of checkpoint that assesses the growth status of imaginal tis- control, cells regulate their own size, through modulating the sues, primordia that give rise during metamorphosis to adult uptake of raw materials and the synthesis of new cellular com- body structures (Rewitz et al. 2013). Imaginal disc damage or ponents, and their number, by controlling cell proliferation growth retardation inhibits ecdysone production, and thus and apoptosis. induces a delay in pupariation to allow regeneration and At the finest level of growth and proliferation control, each compensatory growth, thereby maintaining proper organ cell must sense its own metabolite levels and use these data to proportions. Recently, DILP8 was identified as the hormone evaluate whether it possesses the necessary raw ingredients released
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