Insulin-like peptides encode sensory information to regulate "C. elegans" development

The sensory system senses and conveys information about an animal’s complex environment to induce the optimal physiological and behavioral responses that are necessary for survival. Sensory information is transduced within neurons and downstream target tissues through a variety of molecular signaling pathways. One such pathway is the insulin-like signaling pathway, which is not only a key regulator of growth and metabolism in many species but also of other biological processes that are influenced by sensory inputs.
In the nematode worm C. elegans, the insulin-like pathway is part of the signaling network that mediates the sensory influence on development and lifespan. C. elegans is predicted to have 40 genes that encode insulin-like peptides (ILPs), many of which are expressed in sensory neurons and interneurons, as well as in other tissues. Thus, insulin-like peptides are likely candidates to regulate C. elegans physiology in response to environmental cues by modulating the activities of the affected sensory circuits and/or their target tissues.
During the first larval stage, an important developmental decision is made between reproductive growth and a larval arrest program, also known as the dauer program. In response to harsh environmental cues, worms enter the stress-resistant dauer (endurance) stage, from which they exit when environmental cues again favor reproductive development. This developmental decision is known to be mediated not only by specific sensory neurons but also by insulin-like signaling. Considering the complexity of the sensory cues that regulate this developmental switch and the number of ILPs that are expressed in different sensory neurons, I hypothesize that ILPs encode sensory information to regulate C. elegans development.
For my thesis, I have tested this hypothesis by focusing on three ILPs, daf-28, ins 6 and ins-1, which have been implicated in the regulation of dauer arrest through gain-of-function and RNA-interference analyses. Since these previous studies have only indirectly examined ILP function, which prevents the direct comparison of the relative contributions of each ILP in regulating this process, I have used deletion mutants, in which ILP function is specifically and completely eliminated. Such an approach has allowed me to examine directly and define the precise functions of these ILPs in regulating the different steps of the developmental switch in response to specific sensory cues.
In contrast to the earlier studies, I show that these ILPs have distinct, non-redundant functions in controlling this switch in development. While ins-1 is necessary for dauer arrest, daf-28 and ins-6 are required for reproductive growth. I find that daf-28 has a major function in inhibiting dauer entry, while ins-6 has only a minor role in this process. However, the relative importance of these two ILPs is reversed in the regulation of dauer exit: ins-6 now has a major function in promoting dauer exit, whereas daf-28 has only a minor role.
To regulate the developmental switch, these ILPs generate precise responses to dauer-inducing sensory cues, like low food availability or high levels of a pheromone mixture that signals overcrowding. While daf-28 expression has been shown to be downregulated by either high pheromone or low food levels in sensory neurons that regulate the switch, I do not observe any such regulation for ins-1 expression in the same neurons. At the same time, I also find that during reproductive growth ins-6 is expressed in sensory neurons (ASI) that inhibit dauer entry, whereas ins-6 transcription shifts during dauer arrest to another pair of sensory neurons (ASJ) that promote dauer exit, a change that persists in post-dauer adults. I further show that ins-6 expression in ASI is specifically downregulated by the dauer pheromone mixture and not by food levels, whereas the switch in expression to ASJ requires both the dauer pheromones and the full induction of the dauer program. Thus, the specificity in the stimulus regulation of ilp expression in sensory neurons suggests a mechanism through which these ILPs encode sensory information and regulate development in a combinatorial fashion.