Moria Ben Yishay

In the nematode Caenorhabditis elegans, the heat shock response (HSR) is regulated at the organismal level by a network of thermosensory neurons that senses elevated temperatures and activates the HSR in remote tissues. Which neuronal receptors are required for this signaling mechanism and in which neurons they function are largely unanswered questions. Here we used worms that were engineered to exhibit RNA interference hypersensitivity in neurons to screen for neuronal receptors that are… Show more

In the nematode Caenorhabditis elegans, the heat shock response (HSR) is regulated at the organismal level by a network of thermosensory neurons that senses elevated temperatures and activates the HSR in remote tissues. Which neuronal receptors are required for this signaling mechanism and in which neurons they function are largely unanswered questions. Here we used worms that were engineered to exhibit RNA interference hypersensitivity in neurons to screen for neuronal receptors that are required for the activation of the HSR and identified a putative G-protein coupled receptor (GPCR) as a novel key component of this mechanism. This gene, which we termed GPCR thermal receptor 1 (gtr-1), is expressed in chemosensory neurons and has no role in heat sensing but is critically required for the induction of genes that encode heat shock proteins in non-neural tissues upon exposure to heat. Surprisingly, the knock-down of gtr-1 by RNA interference protected worms expressing the Alzheimer's-disease-linked aggregative peptide Aβ3-42 from proteotoxicity but had no effect on lifespan. This study provides several novel insights: (1) it shows that chemosensory neurons play important roles in the nematode's HSR-regulating mechanism, (2) it shows that lifespan and heat stress resistance are separable, and (3) it strengthens the emerging notion that the ability to respond to heat comes at the expense of protein homeostasis (proteostasis). Show less

Reducing the activity of the insulin/IGF-1 signaling pathway (IIS) modifies development, elevates stress resistance, protects from toxic protein aggregation (proteotoxicity), and extends lifespan (LS) of worms, flies, and mice. In the nematode Caenorhabditis elegans, LS extension by IIS reduction is entirely dependent upon the activity of the transcription factors DAF-16 and the heat shock factor-1 (HSF-1). While DAF-16 determines LS exclusively during early adulthood, it is required for… Show more

Reducing the activity of the insulin/IGF-1 signaling pathway (IIS) modifies development, elevates stress resistance, protects from toxic protein aggregation (proteotoxicity), and extends lifespan (LS) of worms, flies, and mice. In the nematode Caenorhabditis elegans, LS extension by IIS reduction is entirely dependent upon the activity of the transcription factors DAF-16 and the heat shock factor-1 (HSF-1). While DAF-16 determines LS exclusively during early adulthood, it is required for proteotoxicity protection also during late adulthood. In contrast, HSF-1 protects from proteotoxicity during larval development. Despite the critical requirement for HSF-1 for LS extension, the temporal requirements for this transcription factor as a LS determinant are unknown. To establish the temporal requirements of HSF-1 for longevity assurance, we conditionally knocked down hsf-1 during larval development and adulthood of C. elegans and found that unlike daf-16, hsf-1 is foremost required for LS determination during early larval development, required for a lesser extent during early adulthood and has small effect on longevity also during late adulthood. Our findings indicate that early developmental events affect LS and suggest that HSF-1 sets during development of the conditions that enable DAF-16 to promote longevity during reproductive adulthood. This study proposes a novel link between HSF-1 and the longevity functions of the IIS. Show less