Many animals possess neurons specialized for the detection of carbon dioxide (CO2), which acts as a cue to elicit behavioral responses and is also an internally generated product of respiration that regulates animal physiology. In many organisms how such neurons detect CO2 is poorly understood. We report here a mechanism that endows C. elegans neurons with the ability to detect CO2. The ETS-5 transcription factor is necessary for the specification of CO2-sensing BAG neurons. Expression of a single ETS-5 target gene, gcy-9, which encodes a receptor-type guanylate cyclase, is sufficient to bypass a requirement for ets-5 in CO2-detection and transforms neurons into CO2-sensing neurons. Because ETS-5 and GCY-9 are members of gene families that are conserved between nematodes and vertebrates, a similar mechanism might act in the specification of CO2-sensing neurons in other phyla.

Animal behavior is shaped through interplay among genes, the environment, and previous experience. As in mammals, satiety signals induce quiescence in Caenorhabditis elegans. Here we report that the C. elegans transcription factor ETS-5, an ortholog of mammalian FEV/Pet1, controls satiety-induced quiescence. Nutritional status has a major influence on C. elegans behavior. When foraging, food availability controls behavioral state switching between active (roaming) and sedentary (dwelling) states; however, when provided with high-quality food, C. elegans become sated and enter quiescence. We show that ETS-5 acts to promote roaming and inhibit quiescence by setting the internal "satiety quotient" through fat regulation. Acting from the ASG and BAG sensory neurons, we show that ETS-5 functions in a complex network with serotonergic and neuropeptide signaling pathways to control food-regulated behavioral state switching. Taken together, our results identify a neuronal mechanism for controlling intestinal fat stores and organismal behavioral states in C. elegans, and establish a paradigm for the elucidation of obesity-relevant mechanisms.ETS transcription factor | neuronal signaling | satiety | fat levels | quiescence A nimal behavior is strongly influenced by the availability of food. In invertebrates and vertebrates, appetite, locomotor activity, and sleep rhythms are all driven by nutritional state (1-7). When malnourished, animals seek out a new food source by actively exploring their environment (roaming), whereas animals that are well fed tend to explore less (dwelling) and when fully sated enter a quiescent or sleep-like state (1-3, 8, 9). Transitions between these behavioral states can be regulated by sensory perception of external stimuli and through gut signals or other internal cues that are generated according to food quality (3,4,6).Initial evidence for neuronal regulation of feeding behavior was shown in mammals using hypothalamic lesions (10). Sectioning of specific regions within the rat hypothalamus evoked opposing behaviors. Removal of one section caused overeating and obesity, whereas removal of an adjacent section resulted in starvation owing to reduced eating (10). Subsequent studies showed that the pro-opiomelanocortin-expressing neurons in the hypothalamus function to suppress feeding, whereas a hypothalamic region that contains neuropeptide Y/agouti-related protein-expressing neurons promotes feeding (11). These adjacent brain regions integrate signals received from the gut that report satiety (12). The nutritive content of food itself also serves as a potent regulator of behavior. In mammals, a diet loaded with fats and sugars stimulates overfeeding and leads to obesity (13). In addition, rats can learn to select a source of food based exclusively on its nutritional value in the absence of external cues (14).In Caenorhabditis elegans, as in mammals, nutritive value is a behavioral stimulus (1, 4). Nematodes exhibit different behaviors when cultured on low-quality food compared to high-quality...

Animals harbor specialized neuronal systems that are used for sensing and coordinating responses to changes in oxygen (O2) and carbon dioxide (CO2). In Caenorhabditis elegans, the O2/CO2 sensory system comprises functionally and morphologically distinct sensory neurons that mediate rapid behavioral responses to exquisite changes in O2 or CO2 levels via different sensory receptors. How the diversification of the O2- and CO2-sensing neurons is established is poorly understood. We show here that the molecular identity of both the BAG (O2/CO2-sensing) and the URX (O2-sensing) neurons is controlled by the phylogenetically conserved SoxD transcription factor homolog EGL-13. egl-13 mutant animals fail to fully express the distinct terminal gene batteries of the BAG and URX neurons and, as such, are unable to mount behavioral responses to changes in O2 and CO2. We found that the expression of egl-13 is regulated in the BAG and URX neurons by two conserved transcription factors—ETS-5(Ets factor) in the BAG neurons and AHR-1(bHLH factor) in the URX neurons. In addition, we found that EGL-13 acts in partially parallel pathways with both ETS-5 and AHR-1 to direct BAG and URX neuronal fate respectively. Finally, we found that EGL-13 is sufficient to induce O2- and CO2-sensing cell fates in some cellular contexts. Thus, the same core regulatory factor, egl-13, is required and sufficient to specify the distinct fates of O2- and CO2-sensing neurons in C. elegans. These findings extend our understanding of mechanisms of neuronal diversification and the regulation of molecular factors that may be conserved in higher organisms.

Animals harbor specialized neuronal systems that are used for sensing and coordinating responses to changes in oxygen (O 2 ) and carbon dioxide (CO 2 ). In Caenorhabditis elegans, the O 2 /CO 2 sensory system comprises functionally and morphologically distinct sensory neurons that mediate rapid behavioral responses to exquisite changes in O 2 or CO 2 levels via different sensory receptors. How the diversification of the O 2 -and CO 2 -sensing neurons is established is poorly understood. We show here that the molecular identity of both the BAG (O 2 /CO 2 -sensing) and the URX (O 2 -sensing) neurons is controlled by the phylogenetically conserved SoxD transcription factor homolog EGL-13. egl-13 mutant animals fail to fully express the distinct terminal gene batteries of the BAG and URX neurons and, as such, are unable to mount behavioral responses to changes in O 2 and CO 2 . We found that the expression of egl-13 is regulated in the BAG and URX neurons by two conserved transcription factors-ETS-5(Ets factor) in the BAG neurons and AHR-1(bHLH factor) in the URX neurons. In addition, we found that EGL-13 acts in partially parallel pathways with both ETS-5 and AHR-1 to direct BAG and URX neuronal fate respectively. Finally, we found that EGL-13 is sufficient to induce O 2 -and CO 2 -sensing cell fates in some cellular contexts. Thus, the same core regulatory factor, egl-13, is required and sufficient to specify the distinct fates of O 2and CO 2 -sensing neurons in C. elegans. These findings extend our understanding of mechanisms of neuronal diversification and the regulation of molecular factors that may be conserved in higher organisms.