Eyeless light sensing promotes thermotolerance

In transient environments, organisms employ homeostatic mechanisms to enhance survival and species propagation. A recent study in Cell Research revealed that light perception by the eyeless organism Caenorhabditis elegans coordinates independent serotonin-mediated mechanisms to promote survival, reproductive timing and species fitness strategies to withstand thermal stress.

The ability to sense and respond to environmental stress is critical for organisms to adapt and maintain homeostasis. Recognition of specific external cues by sensory neurons, acting as first responders, enables environment-specific homeostatic mechanisms to be initiated. The nematode Caenorhabditis elegans is an excellent model to study homeostasis due to its facile genetics and deep conservation of neuronal signaling and stress response pathways. In nature, C. elegans is exposed to fluctuations in temperature, humidity, light, food, oxidative stress and bacterial pathogens. Integration of these environmental stressors requires sophisticated sensory signaling mechanisms that can be investigated genetically in the laboratory.

C. elegans was previously shown to detect and mount an avoidance response to high-intensity light, despite being eyeless.^1,2 Light sensing is achieved by the neuronally-expressed seven-transmembrane photoreceptors, LITE-1 and GUR-3.^1,2 In a recent study, Zhou and Liu asked whether perception of low-intensity light, that resembles natural sunrise conditions, had any physiological importance.³

C. elegans were exposed to a 24-h light-dark cycle prior to 1 h of dark or low-intensity light, followed by exposure to multiple independent physiological stressors. Light exposure increased thermotolerance over a broad range of temperatures. In contrast, light exposure did not enhance tolerance to oxidative, mitochondrial or pathogen-related stress, suggesting a specific mechanism underpinning light-induced thermotolerance. A preceding phase of darkness was critical for thermotolerance, and importantly light exposure did not cause a significant change in ambient temperature, ruling out a role for heat preconditioning. The authors revealed that the LITE-1 photoreceptor, but not GUR-3, is required for light-induced thermotolerance. Further, cell ablation, cell-specific rescue, and optogenetic experiments revealed that LITE-1 acts in the pair of ASK sensory neurons to drive light-induced thermotolerance.

Heat stress survival requires upregulation of conserved heat shock proteins (HSPs) through pathways controlled by insulin-like signaling, the HSF-1 transcription factor and the AFD thermosensory neurons.^4,5 Light exposure promoted HSP expression under heat stress; and HSP induction was dependent on the LITE-1 photoreceptor and the HSF-1 branch of thermoregulation. Light-induced thermotolerance depended on HSF-1 expression in body wall muscle and the intestine, suggesting the presence of a signaling mechanism linking the ASK sensory neurons to these peripheral tissues.

How do the ASK sensory neurons communicate light cues to the periphery to promote thermotolerance? Using genetic mutant analysis, neuromodulator exposure, expression analysis, and cell ablation, the authors revealed that serotonin derived from the ADF sensory neurons, acting downstream of the ASK neurons, is critical for light-induced thermotolerance. Further, TGF-β signaling and innexin INX-10 contribute to communication between ASK and ADF.

Additional screening of serotonin receptor mutants identified the G-protein-coupled receptor SER-5, ortholog of mammalian 5-HT6, acting in body wall muscle and the intestine to promote light-induced thermotolerance. Downstream of SER-5, the G proteins GSA-1 and GPA-12 (also acting in body wall muscle and the intestine) were identified as critical for light-induced thermotolerance. Together, this analysis identified a signaling pathway from sensory neuron to peripheral tissues, where light exposure promotes organismal survival under thermal stress.

Does light exposure promote other survival-promoting mechanisms? To answer this question, Zhou and Liu investigated two other outputs: egg-laying and population fitness. The authors found that embryos retained in the maternal uterus have enhanced thermotolerance compared to those already laid. They hypothesized that light exposure may delay egg-laying to enhance embryo survival to heat stress. Indeed, they found that switching from dark to light reduced egg-laying whereas a light to dark shift increased egg-laying. These light-induced changes in egg-laying behavior were dependent on the LITE-1 photoreceptor and downstream serotonin signaling. In this case, however, the SER-7 serotonin receptor acting in vulval muscle coordinates light-induced egg-laying. As slowing egg-laying rate only postpones embryonic exposure to high temperatures, the authors investigated whether potential intergenerational protective mechanisms also exist. Intriguingly, they found that the progeny of adults exposed to light exhibit enhanced thermotolerance. This survival effect required maternal light perception through the LITE-1 photoreceptor. Serotonin is also critical for this intergenerational effect, with the SER-1 serotonergic receptor acting in the germline as a downstream effector. How SER-1 acts in the germline to promote intergenerational fitness is an important future question to address. Using population assays, the authors finally showed that light-induced thermotolerance provides a competitive advantage, especially in conditions of food scarcity. This highlights light perception as an important cue that enables organisms to initiate appropriate homeostatic mechanisms in ephemeral habitats.

In summary, Zhou and Liu identified a key broadcast molecule that drives different light-induced thermoprotective mechanisms — serotonin. Intriguingly, each light-induced effect engages different serotonin receptors that have distinct functional locales: SER-1 (intergenerational thermotolerance — acting in the germline), SER-5 (thermotolerance — acting in the intestine and muscle), SER-7 (egg-laying — acting in vulval muscle) (Fig. 1). Previous research also identified serotonin as a critical regulator of the systemic mitochondrial stress response, highlighting the importance of this conserved neuromodulator in homeostatic regulation.⁶ However, the identification of highly complex serotonin-dependent regulatory mechanisms governing behavior⁷ suggests that the understanding of how serotonin controls physiology is in its infancy.

Fig. 1: Schematic diagram of cascading light-induced serotonin signaling routes to coordinate thermotolerance.

Sunlight sensed by the LITE-1 photoreceptor coordinates inter-tissue serotonergic signals, acting through distinct receptors (SER-1, SER-5 and SER-7) in different locales to promote intergenerational fitness, thermotolerance and egg-laying.