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, 2 (12), 340-361

Systemic Signalling and Local Effectors in Developmental Stability, Body Symmetry, and Size


Systemic Signalling and Local Effectors in Developmental Stability, Body Symmetry, and Size

Sergio Juarez-Carreño et al. Cell Stress.


Symmetric growth and the origins of fluctuating asymmetry are unresolved phenomena of biology. Small, and sometimes noticeable, deviations from perfect bilateral symmetry reflect the vulnerability of development to perturbations. The degree of asymmetry is related to the magnitude of the perturbations and the ability of an individual to cope with them. As the left and right sides of an individual were presumed to be genetically identical, deviations of symmetry were traditionally attributed to non-genetic effects such as environmental and developmental noise. In this review, we draw attention to other possible sources of variability, especially to somatic mutations and transposons. Mutations are a major source of phenotypic variability and recent genomic data have highlighted somatic mutations as ubiquitous, even in phenotypically normal individuals. We discuss the importance of factors that are responsible for buffering and stabilizing the genome and for maintaining size robustness and quality through elimination of less-fit or damaged cells. However, the important question that arises from these studies is whether this self-correcting capacity and intrinsic organ size controls are sufficient to explain how symmetric structures can reach an identical size and shape. Indeed, recent discoveries in the fruit fly have uncovered a conserved hormone of the insulin/IGF/relaxin family, Dilp8, that is responsible for stabilizing body size and symmetry in the face of growth perturbations. Dilp8 alarm signals periphery growth status to the brain, where it acts on its receptor Lgr3. Loss of Dilp8-Lgr3 signaling renders flies incapable of detecting growth perturbations and thus maintaining a stable size and symmetry. These findings help to understand how size and symmetry of somatic tissues remain undeterred in noisy environments, after injury or illnesses, and in the presence of accumulated somatic mutations.

Keywords: Dilp8; IGF; Lgr3; buffering; developmental stability; environmental stress; fluctuating asymmetry; neuroendocrine signaling; relaxin; robustness; somatic mutations.

Conflict of interest statement

Conflict of interest: The authors declare that there are no conflicts of interest related to the subject discussed in this review.


Figure 1
Figure 1. FIGURE 1: A speculative model of the three sources of perturbation and their interactions in generating intra- and interindividual phenotypic variability, illustrated in flies.
(A) Drosophila larvae may acquire mutations that can be expressed in a mosaic state (brown dots) or inherited from one of the parents (all brown). Stochastic noise may cause gene expression fluctuations and variability in growth between the left and right sides. Environmental factors may cause changes in gene expression by genetic and non-genetic effects. Biological noise can cause replication errors that result in mutations e.g. [61] and thus it may also contribute to somatic mutations. (B) Developmental robustness requires mechanisms that sense damage and growth perturbations inflicted at the cell, organ, and systemic level. Specific damage sensors activate coordinated responses that trigger checkpoints such as transcriptional or cell cycle arrest to provide time for repair or to counterbalance perturbations (e.g., during a thermal stress). When damage is unrepairable, cellular stress sensors also initiates the apoptosis of the damaged cells. To maintain tissue growth and homeostasis, stress sensors such as p53 trigger compensatory proliferation. Massive tissue damage activates local regenerative responses and trigger a checkpoint that delays developmental timing (maturation) and act systemically. In addition, a variety of surveillance mechanisms maintain tissue quality control by detecting and eliminating both less fit and potentially harmful cells.
Figure 2
Figure 2. FIGURE 2: Neuroendocrine control of symmetry and body size.
(A) Loss of the Dilp8 hormone yields flies with variable body sizes (inter-individual) and increased bilateral asymmetry (intraindividual variability). (B) Feeding Drosophila juveniles with the DNA-damaging agent ethyl methanosulfonate (EMS) induces massive cell death in the imaginal discs, cell cycle arrest, and strong developmental delay. Without dilp8 (bottom wing), EMS-fed animals cannot recover from this damage and exhibit a 6-fold increase in pattern and growth inaccuracies [14]. (C) dilp8 mutants exhibit left-right wing asymmetry and also pattern inaccuracies, which may reflect the unmasking of pre-existing or acquired mutations, stochastic noise, and/or the negative effect of the environment (e.g., temperature stress). (D) Dilp8 produced by damaged or growth-perturbed cells, which also activates the production of other ‘alarm' signals such as retinoid signals [145] is released to circulation and acts in the brain through the relaxin receptor Lgr3 (green neurons). Lgr3 co-regulates two neuronal populations which control growth and maturation rate by acting on the ring gland. The ring gland is a central neuroendocrine organ regulating organismal growth rate and timing of maturation [45]. Distinct groups of cells within the ring gland — the corpus allatum — produce the juvenile hormone (JH), and cells of the prothoracic gland synthesise and release the steroid hormone ecdysone. Its complex functions are centrally controlled by neurons that produce the prothoracicotropic hormone (PTTH; represented as blue circles) [139,146] and the insulin-producing cells (IPCs; red circles). IPCs produce insulin-like peptides, primarily Dilp2, Dilp3, and Dilp5, and regulate systemic growth and ecdysone biosynthesis (reviewed in [47].

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