Feedback is welcome
Analysis of insulin-like signaling in C. elegans reveals extensive positive and negative feedback regulation.
The insulin-like signaling system of nematode worms is comparable to that of more complex organisms; it helps regulate a wide range of the animal’s biology, including metabolism, growth, and development. This system is remarkably flexible, with the ability to maintain a physiological steady-state (homeostasis) while also controlling switches between quite different developmental fates (developmental plasticity). A report published in GENETICS reveals the pervasive involvement of both positive and negative feedback in regulating this master pathway in the model nematode Caenorhabditis elegans.
The C. elegans genome encodes one insulin-like receptor and 40 insulin-like signaling proteins. The activity of insulin-like peptides can, in turn, affect the expression of these peptides themselves, yet exactly how this signaling network is regulated remains ambiguous. Kaplan et al. explored the extent of the feedback mechanisms of insulin-like signaling, along with their dependence on nutrient availability.
The worm insulin-like receptor, DAF-2, signals through antagonizing the activity of the transcription factor DAF-16, the nematode ortholog of mammalian FoxO. Because of these opposing functions, daf-2– and daf-16-mutant nematodes were employed to observe how changes in insulin-like signaling affect the expression of insulin-like genes.
Using these mutants under multiple conditions, such as fed vs. starved larval worms, the authors analyzed the expression of insulin-like genes, along with other genes involved in insulin-like signaling, like those in the PI3K pathway.
The authors found extensive feedback regulations within insulin-like signaling; the expression of nearly all detectable insulin-like genes was affected by altering insulin-like signaling, as were some components of the PI3K pathway. These feedback mechanisms were extensive and complex; for example, the well-studied insulin-like protein DAF-28, an agonist of DAF-2, seems to be repressed by DAF-16—thus, DAF-28 is a positive regulator of its own transcription, since activating DAF-2 represses DAF-16.
Overall, considerable evidence for both negative and positive feedback of insulin-like signaling was found; the authors write that this is likely to allow for rapid response to stimuli—like food availability—while still maintaining homeostasis. Further studies will be needed to delve into the precise molecular mechanisms of such feedback systems and to explore similar regulation in other organisms.
Pervasive Positive and Negative Feedback Regulation of Insulin-Like Signaling in Caenorhabditis elegans
Rebecca E. W. Kaplan, Colin S. Maxwell, Nicole Kurhanewicz Codd, L. Ryan Baugh
GENETICS January 2019 211: 349-361; https://doi.org/10.1534/genetics.118.301702