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

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

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