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Growth control through regulation of insulin-signaling by nutrition-activated steroid hormone

Kurt Buhler, Jason Clements, Mattias Winant, Veerle Vulsteke, Patrick Callaerts

Preprint posted on 13 December 2017 https://www.biorxiv.org/content/early/2017/12/13/234088

Article now published in Development at http://dx.doi.org/10.1242/dev.165654

Activation of steroid hormone in fly larva’s fat body requires nutrition and promotes insulin-dependent larval growth via brain and trachea

Selected by Alberto Rosello-Diez

Categories: developmental biology

Background

Developmental success in a changing environment requires that developing organs respond to external inputs. Growth and maturation, for example, depend on nutrient availability. This topic has been fruitfully explored in fruitflies (pun intended), where metamorphosis is delayed if the larva has not grown enough. Insulin/insulin-like signalling (IIS) and steroid signalling (SS) are the main players in the nutrition-dependent control of larval growth (both IIS and SS) and eventual metamorphosis (SS), but how and where they intersect to keep growth and maturation coordinated remains incompletely unknown.

Key findings

Buhler et al. make three important discoveries that move this field forwards:
– Nutrition controls the last synthetic step of the steroid 20-hydroxyecdysone (20E) in the fat body (the functional equivalent of liver and adipose tissue, the purple region in the figure), and genetic impairment of 20E production in this tissue leads to a maturation delay and reduced systemic growth, associated with reduced systemic IIS.
– The authors warn that a commonly used IPC driver is also active in the trachea (blue network in the figure), which might lead to reinterpretation of previous experiments. In fact, they show that impairment of 20E signalling only in the insulin-producing cells (IPCs) of the brain, heretofore considered the main link between SS and IIS, leads only to a mild growth reduction. Fully reduced growth and IIS takes place when 20E signalling is reduced both in the IPCs and the larval trachea, which also expresses 20E receptors.
– The multiple downstream molecules involved in 20E signalling can have opposite effects on growth, depending on their position in the cascade (later steps tend to inhibit growth in a potential feedback loop) and the tissue where they act (deletion in the trachea frequently masks the effect of deletion in the IPCs).

What I like about this preprint

Buhler et al. bring a breath of fresh air into the link between nutrition and growth, most remarkably uncovering a tissue –the trachea– that was not suspected to play any role. This study opens up exciting new research avenues and calls for reinterpretation of previous growth studies that used drivers with potential tracheal expression.

Figure 8 from Buhler et al. Reproduced with permission.

Pending questions

– Buhler et al. show that forced biosynthesis of 20E in the fat body of starved larvae rescues levels of some insulin-like peptides and wet weight, but not dry weight. Elucidating the exact growth contribution of each of the nutrient-affected tissues and pathways will require future studies.

– It was previously shown that hypoxia has a severe effect on larval growth acting through IPCs (Wong et al. 2014). Together with this study, these results suggest that it is the trachea that mainly responds to 20E to control IPC activity. This could be tested by trying to rescue hypoxic larvae (or larvae with diminished 20E receptor expression in the trachea) with 20E supplementation.

– The authors thoroughly characterize expression of nuclear receptors in IPCs, but I wonder what the repertoire is in cells of the trachea. Moreover, what happens when the 20E signal transduction machinery is systematically perturbed using trachea-specific drivers?

– A recent zebrafish study showed that reoxygenation-induced catch-up growth after hypoxia requires insulin signalling in neural crest cells (Kamei et al. 2017), suggesting that some of the links between nutrition, growth and hypoxia are conserved in vertebrates. I wonder whether the lungs play an unsuspected role in the coordination of growth and maturation.

 

Related research
1.Insulin- and warts-dependent regulation of tracheal plasticity modulates systemic larval growth during hypoxia in Drosophila melanogaster. Wong DM, Shen Z, Owyang KE, Martinez-Agosto JA. PLoS One. 2014 Dec 26;9(12):e115297
2. Catch-up growth in zebrafish embryo requires neural crest cells sustained by Irs1-signaling. Hiroyasu Kamei, Yosuke Yoneyama, Fumihiko Hakuno, Rie Sawada, Toshiaki Shimizu, Cunming Duan, Shin-Ichiro Takahashi. Endocrinology, en.2017-00847, https://doi.org/10.1210/en.2017-00847

 

Tags: drosophila

Posted on: 7 February 2018 , updated on: 19 February 2018

Read preprint (3 votes)

Author's response and 'the story behind the story'

Kurt Buhler shared

  • Questioning whether hypoxia rescue will revert phenotypes is interesting to consider. Providing a controlled, hyperoxic environment could prove challenging for Drosophila larvae, but is hypothetically possible. However, one could be more inclined to look internally toward tracheal morphology, and a potential role that 20E signalling plays in tracheal remodelling and development during ecdysis. Given that the trachea morphology and branching needs to expand with total body size during ecdysis and potentially also growth, one could hypothesize that 20E signalling is important to facilitate these morphological changes in parallel with others occuring during the rise in 20E titres at ecdysis between larval stages. We noted that without tracheal silencing of the Dilp2-GAL4 , phenotypes arose after the L2-L3 transition, pointing to an essential role of 20E during this period. Be it a functional or structural requirement – or both.
  • We have tried to disrupt 20E signalling nuclear receptors using tracheal drivers such as btl-GAL4 . The result is complete embryonic lethality while reared at 25 degrees, which is unsurprising given that 20E is known to be essential during embryonic tracheal morphogenesis ( Chavoshi & Moussian, 2010 ). However, conducting these experiments at lower temperatures of 18 degrees, which reduce GAL4 transcriptional activator expression and activity, results in smaller animals. This phenocopies the size phenotype observed with dilp2-GAL4 without tracheal silencing. Future experiments using temporally controlled knockdown of 20E nuclear receptors in the trachea, for example using the temperature-sensitive GAL80t s together with tracheal drivers, could better elucidate this potential larval requirement of these nuclear receptors in the trachea.

In short, this story personifies my personal experiences with work-life balance in academia. The initial results were obtained using a lot of unhealthy working habits, like sleeping in the lab and exhaustive working hours driven by a compulsive emotional need for results and success. Imbalance between work and life led to a fatigue and erosion of my happiness. In a lot of ways, work and out-of-work life are a lot like growth and maturation- opposing, energy-intensive processes requiring precise balance in response to many internal and external contexts. Though this all culminated with the discovery of the tracheal expression of the dilp2-GAL4 – thanks to a ‘difficult’ reviewer to whom I am now very thankful. The knowledge that much of my work was derived from a faulty tool and a semantic false positive was at the time – for lack of a better word – suffocating.

Furthering this curtain pull was the startling revelation that tracheal activity of GAL4 drivers appears to not be exclusive to the dilp2-GAL4, but affects many different drivers. The implications for the body of published literature using these drivers was, to say the least, daunting. How many phenotypes can be explained due to unintentional genetic perturbations of the trachea?

It was too that during this time, while elaborating on how nutrition controls shade, I realized that most departments with fly labs use completely different fly food recipes. Given the essential role of nutrition in most physiological processes, one can hypothesize that lack of standardization in this area could underly some of the reproducibility difficulties commonly experienced by many fly researchers, today.

However, as we chipped away at the mountain of work that was repeating a lot of these experiments and resolving the role of the trachea in this regulation – and what 20E was actually doing in the IPCs – things became more clear. Not only with respect to the possible role of the trachea in growth regulation, but also with the subtler role of 20E in the IPCs. By then, I had a healthier perspective on life in the lab, and a balance with life outside it. Much like the interaction between growth and maturation, which still requires room to breathe.

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