Because life is often unpredictable, dynamic, and complex, all animals have evolved remarkable abilities to cope with changes in their external environment and internal physiology. This regulatory plasticity leads to shifts in behavior and metabolism, as well as to changes in development, growth, and reproduction, which is thought to improve the chances of survival and reproductive success. In favorable environments, the nematode Caenorhabditis elegans develops rapidly to reproductive maturity, but in adverse environments, animals arrest at the dauer diapause, a long-lived stress resistant stage. A molecular and genetic analysis of dauer formation has revealed key insights into how sensory and dietary cues are coupled to conserved endocrine pathways, including insulin/IGF, TGF-, serotonergic, and steroid hormone signal transduction, which govern the choice between reproduction and survival. These and other pathways reveal a molecular basis for metazoan plasticity in response to extrinsic and intrinsic signals.All living things can sense change in their environment and physiologic milieu and adapt accordingly, revealing remarkable plasticity. Changes in behavior and metabolism are well-recognized forms of plasticity, which are typically rapid and geared to maintain organismal homeostasis. Sustained environmental challenge, such as nutrient limitation, stress, and shifts in photoperiod or temperature, can culminate in long lasting changes in metabolism, behavior, growth, and development, most dramatically resulting in alternate life strategies, such as hibernation, or diapause, a state of developmental arrest. Moreover, restricted dietary intake can delay reproduction and extend organismal life span in diverse species. Collectively, these patterns and their variations comprise an animal's life history. Although determined by genotype, life history traits are largely regulated and plastic, not passively dictated by resource availability. This view is supported by the discovery of myriads of regulatory layers, including neural signaling, hormones, and signal transduction pathways that form logical circuits governing these traits.Despite its invariant cellular development (Sulston 1988), the worm Caenorhabditis elegans reveals evident plasticity in its life history, which ultimately enhances its chance of survival through environmental hazards, and ensures that somatic growth and reproduction match available resources. Notably, in favorable environments, C. elegans will develop rapidly to reproductive maturity, but in unfavorable environments, animals will arrest at the dauer diapause, a larval stage geared for survival (Fig. 1A). A genetic analysis of C. elegans dauer formation has illuminated how environmental and dietary cues are coupled to evolutionarily conserved molecular pathways, including neurosensory, TGF-, insulin/IGF, serotonergic, and steroid hormone signal transduction, which impact growth, metabolism, maturation, survival, and aging. These and related studies have led to key insights into similar pro...
In response to small molecule signals such as retinoids or steroids, nuclear receptors activate gene expression to regulate development in different tissues. microRNAs turn off target gene expression within cells by binding complementary regions in mRNA transcripts, and they have been broadly implicated in development and disease. Here we show that the C. elegans nuclear receptor DAF-12 and its steroidal ligand directly activate promoters of let-7 microRNA family members to downregulate the microRNA target hbl-1 and drive progression of epidermal stem cells from second to third larval stage patterns of cell division. Conversely, the unliganded receptor represses microRNA expression during developmental arrest. These findings identify microRNAs as components of a hormone-coupled molecular switch that shuts off earlier developmental programs to allow for later ones.Lipophilic hormones coordinate organism-wide developmental progression in metazoans by binding to nuclear hormone receptors (NHR), converting the presence or absence of ligand into changes in gene expression patterns(1). This regulation is conserved in the nematode C. elegans, where the nuclear hormone receptor (NHR) DAF-12, a homolog of vertebrate liver-X and vitamin D receptors, regulates developmental progression or arrest in response to the environment(2,3). In favorable environments, activation of TGF-β and insulin/IGF signaling cascades result in production of the DAF-12 steroidal ligands, the dafachronic acids (e.g. Δ4-DA), which promote rapid progression through four larval stages (L1-L4) to reproductive adults(4). In unfavorable environments, endocrine systems are suppressed and the unliganded DAF-12 causes arrest at a stress-resistant, long-lived alternative third larval stage, called the dauer diapause (L3d) (5). A more cell-intrinsic level of developmental control is exerted by microRNAs (miRs). miRs are ~20-22nt long RNA molecules that bind to the 3'UTR of target mRNAs and decrease their expression (6-8). Null mutants for several miR genes show tissue-selective failure of progression from one stage-specific program to the next, generally described as heterochronic phenotypes. These phenotypes are most visible in the hypodermis, where hypodermal seam cells undergo invariant asymmetric stem cell division patterns, in which one daughter cell fuses to the hypodermal syncitium whereas the other retains stem cell character and its capacity to divide (9). Only during L2, do seam cells undergo one proliferative division prior to stem cell division, and repetition or loss of this program leads to changes in overall seam cell number
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