To grow or not to grow: nutritional control of development during Caenorhabditis elegans L1 arrest

Abstract

It is widely appreciated that larvae of the nematode Caenorhabditis elegans arrest development by forming dauer larvae in response to multiple unfavorable environmental conditions. C. elegans larvae can also reversibly arrest development earlier, during the first larval stage (L1), in response to starvation. "L1 arrest" (also known as "L1 diapause") occurs without morphological modification but is accompanied by increased stress resistance. Caloric restriction and periodic fasting can extend adult lifespan, and developmental models are critical to understanding how the animal is buffered from fluctuations in nutrient availability, impacting lifespan. L1 arrest provides an opportunity to study nutritional control of development. Given its relevance to aging, diabetes, obesity and cancer, interest in L1 arrest is increasing, and signaling pathways and gene regulatory mechanisms controlling arrest and recovery have been characterized. Insulin-like signaling is a critical regulator, and it is modified by and acts through microRNAs. DAF-18/PTEN, AMP-activated kinase and fatty acid biosynthesis are also involved. The nervous system, epidermis, and intestine contribute systemically to regulation of arrest, but cell-autonomous signaling likely contributes to regulation in the germline. A relatively small number of genes affecting starvation survival during L1 arrest are known, and many of them also affect adult lifespan, reflecting a common genetic basis ripe for exploration. mRNA expression is well characterized during arrest, recovery, and normal L1 development, providing a metazoan model for nutritional control of gene expression. In particular, post-recruitment regulation of RNA polymerase II is under nutritional control, potentially contributing to a rapid and coordinated response to feeding. The phenomenology of L1 arrest will be reviewed, as well as regulation of developmental arrest and starvation survival by various signaling pathways and gene regulatory mechanisms.

Keywords: developmental arrest; diapause; insulin-like signaling; starvation; stress resistance.

Figure 1

Feeding is required to initiate larval development, and hatching in the absence of food causes L1 arrest. Larvae can survive L1 arrest for weeks, and they are resistant to a variety of environmental stresses. Unlike L1 arrest, dauer formation involves an alternative developmental program (indicated by dashed arrows) producing a morphologically modified alternative to the third larval stage. Images were adapted from WormAtlas.org.

Figure 2

Model of the C. elegans insulin-like signaling pathway. There are 40 putative insulin-like peptides in C. elegans, and their secretion is mediated by UNC-31/CAPS and the conserved ATPase ASNA-1. DAF-2/InsR is the sole insulin/IGF receptor in C. elegans, and it signals through a conserved PI3K pathway to antagonize function of DAF-16/FOXO. DAF-16/FOXO activates transcription of genes that promote L1 arrest, dauer formation, stress resistance, and lifespan extension. DAF-16/FOXO is not the only effector of insulin-like signaling (Tullet et al. 2008). DAF-16/FOXO is also regulated by additional factors and signaling pathways (Landis and Murphy 2010). DAF-18/PTEN functions independently of DAF-16/FOXO in the germline (Fukuyama et al. 2006).

Figure 3

Synthesis of the monomethyl branched-chain fatty acid C17ISO is necessary to initiate L1 growth and development. Catabolism of essential, branched-chain amino acids produces the precursors of C15ISO, which is converted into C17ISO by the polyunsaturated fatty acid elongases ELO-5 and ELO-6. The pathway depicted for C15ISO synthesis is incomplete.

Figure 4

Gene expression dynamics during L1 arrest and development. mRNA abundance was analyzed in a pair of staged populations that hatched in the presence (green) or absence (red) of food (E. coli), and the first two principal components are plotted (Baugh et al. 2009). Samples from the starved population were fed to initiate recovery 12 hr after hatching and analyzed 3 hr later (green dashes), and samples from the fed population were starved 12 hr after hatching and analyzed 3 hr later (red dashes). Larvae starved in M9 buffer (black dot; no ethanol) are indistinguishable from larvae starved in S-basal (red; 20 mM ethanol) 3 hr after hatching.