Chauve, Laetitia et al. (2019) International Worm Meeting "Inter-individual variability in neuronal stress creates phenotypic variability."

Marioni, John, Hastings, Janna, Chauve, Laetitia, Biggins, Laura, Todtenhaupt, Pia, Murdoch, Sharlene, Vallejos, Catalina, Casanueva, Olivia

[International Worm Meeting, 2019]

We use isogenic C. elegans to study non-genetic influences on phenotypic heterogeneity. Heat shock proteins (hsps) are collectively controlled by the transcription factor HSF-1 and are essential to maintain protein-folding homeostasis. Despite their essentiality, previous works has shown that upon exposure to stress, hsp induction is variable across worms dictating an individual's ability to both cope with stress and to reproduce. The dose-sensitive and critical nature of these phenotypes for survival, prompted us to study inter-individual transcriptional variability under normal, unstressed conditions. We developed a sensitive high-throughput quantitative PCR method and incorporated a Bayesian statistical approach to accurately quantify inter-individual steady-state transcript variability in single worms. We find that hsp transcripts are highly variable across worms even in the absence of exogenous stress. Surprisingly we observed that in vivo, inter-individual variability stems primarily from head neurons (n-hsp). It has been previously shown that ectopic hsf-1 expression in head neurons (n-hsf-1) protects better against exogenous stress. We find a similar phenotype happens to individual worms with greater number of n-hsps under physiological conditions. In addition, we observe that the number of n-hsps is temperature sensitive, suggesting that neuronal stress could modulate adaptation to ambient temperatures. We find that n-hsps anti-correlate with fat desaturases, known to contribute unsaturated fatty acids (UFAs) to both fat storages and membranes. Negative regulation of UFAs is also caused by n-HSF-1, demonstrating causality. We have identified the neurons and the signals critical to relay information across tissues and propose a model where neurons act as a sensitive thermostat that orchestrates homeo-viscous adaptation. The variable activation of the thermostat at normal ambient temperatures creates phenotypic heterogeneity with potential adaptive value.

Chauve, Laetitia et al. (2021) International Worm Meeting "A neuronal thermostat controls membrane fluidity in C. elegans"

Okkenhaug, Hanneke, Lopez-Clavijo, Andrea, West, Greg, Casanueva, Olivia, Wingett, Steven, Murdoch, Sharlene, Segonds-Pichon, Anne, Masoudzadeh, Fatemeh, Kienberger, Hermine, Wakelam, Michael, Li, Cheryl, Chauve, Laetitia, Kleigrewe, Karin, Hodge, Francesca

[International Worm Meeting, 2021]

Cells adapt to temperature shifts by adjusting lipid desaturation levels and the fluidity of membranes in a process dependent on fatty acid desaturase enzymes, and which is thought to be controlled cell autonomously. We have discovered that subtle, step-wise increments in ambient temperature can lead to the conserved heat shock response being activated in head neurons of C.elegans. This response is exactly opposite to the expression of the lipid desaturase FAT-7 in the worm's gut with respect to temperature. We use neuronal overexpression of hsf-1, the master regulator of the heat shock response, as a tool to study the consequences of the heat shock response in neurons. We find that over-expression of hsf-1, in neurons, causes extensive fat remodeling to occur across tissues. These changes include a decrease in fat-7 desaturase expression and an increase in acid lipase expression in the intestine, as well as a shift in the levels of unsaturated fatty acids in the plasma membrane. These shifts are in line with membrane fluidity requirements to survive in warmer temperatures. This is further supported by our lifespan data showing that neuronal over-expression of hsf-1 is more beneficial at warmer temperatures. Knocking down hsf-1 specifically in neurons revealed that endogenous HSF-1 in neurons is not only sufficient, but also partially necessary to control the fat remodellling response in distal tissues. We find that the cGMP receptor, TAX-2/TAX-4, expressed in a subset of at least six sensory neurons, as well as TGF-beta/BMP signaling, are key players in the transmission of neuronal stress to peripheral tissues. This suggests that a thermostat-based mechanism can centrally coordinate membrane fluidity in response to warm temperatures across tissues in multicellular animals.