Ooi, Felicia et al. (2015) International Worm Meeting "Uncovering the mechanisms by which the neurosensory release of serotonin modulates the Heat Shock Response in Caenorhabditis elegans."

Ooi, Felicia, Prahlad, Veena

[International Worm Meeting, 2015]

Recent advances in the field have established that the Heat Shock Response (HSR) in the nematode Caenorhabditis elegans can be controlled in a cell non-autonomous manner (Prahlad et al, 2008; Prahlad & Morimoto, 2011; Maman et al, 2013; Taylor & Dillin, 2013; van Oosten-Hawle et al, 2013; Kumsta et al, 2014). One mechanism of such cell non-autonomous control is through AFD thermosensory neuronal stimulation of serotonin (5-HT) release from the ADF serotonergic neurons (Tatum et al, 2015). Of note, optogenetic stimulation of 5-HT release can activate HSF-1 and transiently upregulate hsp70 mRNA, even in the absence of actual heat stress or protein misfolding. We have identified SER-1, a 5-HT2-like metabotropic G-protein coupled receptor, as having a role in the HSR signaling pathway downstream of 5-HT release, as ser-1 mutants demonstrate a diminished HSR when subjected to either heat shock or optogenetic stimulation of serotonergic neurons. In contrast to actual heat shock, the excitation-coupled release of 5-HT is sufficient to suppress polyglutamine aggregation in C. elegans muscle cells. These studies establish that neurosensory perception of stress is linked to repair of cellular damage. In addition they suggest that the regulation of HSF-1 by serotonergic signaling may differ from that which occurs during heat shock since the commonly accepted model of HSF-1 activation upon heat shock is thought to be through the titration of chaperones by protein misfolding. We are currently using genetics and RNAi screens to investigate whether and how HSF-1 activation by serotonergic signaling is distinct from that induced upon heat shock.

Prahlad, V. et al. (2017) International Worm Meeting "Serotonergic control of the conserved heat shock factor transcription factor (HSF-1)."

Prahlad, V., Ooi, Felicia

[International Worm Meeting, 2017]

One of the recent developments in the study of protein homeostasis is the discovery that in a metazoan such as Caenorhabditis elegans, the cellular response to protein misfolding is not autonomously controlled by individual cells, but instead is under the regulation of the animals' nervous system. However, the functional significance of such regulation remains to be shown. We have previously shown that serotonergic signaling in C. elegans can activate HSF1-dependent hsp70 expression through cell non-autonomous mechanisms. Serotonin (5-hydroxytryptamine, 5-HT) plays a central role in the neuronal mechanisms of learning and memory that allows organisms to synthesize information from their surroundings to predict danger. We find that olfactory learning in C. elegans mediated by the serotonergic system not only enhances avoidance behaviors to potential threats, but also induces neuronal and non-neuronal cells throughout the organism to increase expression of their molecular chaperones if they subsequently encounter this threat. Specifically, neurosensory training potentiates HSF-1 activity in anticipation of the actual encounter with the stressor, while not in itself, resulting in chaperone expression. Molecular chaperones are subsequently expressed if and when animals encounter the actual stressor. Our data show that serotenergic control of HSF-1 equips C. elegans to better survive environmental dangers by pre-emptively and specifically enhancing cellular homeostasis using the neuronal circuitry underlying memory and learning. We will discuss the mechanisms by which neuronal 5-HT and learning potentiate HSF-1 to enhance chaperone expression.

Manser J (1996) West Coast Worm Meeting "CELL MIGRATION GENE mig-10 CAN ENCODE TWO PROTEINS WITH SIMILARITIES TO A FAMILY OF SH2 DOMAIN PROTEINS"

Manser J

[West Coast Worm Meeting, 1996]

Mutations in mig-10 cause incomplete embryonic migration of neurons CAN, ALM and HSN as well as shortened posterior excretory canals. To define more precisely the role of mig-10 in C. elegans development, we have begun a molecular characterization. We have identified mig-10 coding sequence by transformation rescue of mutant phenotypes and DNA sequencing of ct41 (amber) and e2527 (TTTCAA splice acceptor) mutant alleles. Genomic sequencing by us and the genome consortium (1) initially predicted a MIG-10 product of 650aa's containing a large region (~300 aa's) of similarity with a recently identified family of mammalian SH2 domain proteins, Grb7 and Grb10 (2,3). We call this region of similarity the GM domain (for Grb and Mig). The precise functions of Grb7 and Grb10 are not known, but current evidence supports a role in signal transduction: Grb7 is overexpressed in certain breast cancers where it is bound to the growth factor receptor HER2 (4), while Grb10 can interact with the insulin receptor (5). By sequencing cDNA clones and RT-PCR products, we have identified two SL1-trans-spliced mig-10 transcripts which contain different first exons. One transcript can encode the predicted 650aa MIG-10 product, the other a 667aa isoform. Neither predicted MIG-10 protein contains an SH2 domain, but both share with Grb7 and Grb10 the GM domain, a pleckstrin homology (PH) domain (within the GM domain) and proline-rich sequences. The PH domain is commonly found in signal transduction and cytoskeletal proteins, although its function remains controversial (6). Pro-rich sequences like those found in MIG-10 can bind SH3 domains found in many signaling and cytoskeletal proteins (6). Our mosaic analysis reveals that mig-10 acts cell nonautonomously during development of the excretory canals and suggests a possible focus within descendants of the AB lineage, possibly epidermis. We hypothesize that mig-10 may function in signal transduction and/or cytoskeletal organization outside of motile cells. We are currently undertaking additional experiments to clarify the role of mig-10, including immunolocalization of MIG-10 proteins. 1. Wilson, R. et al. 1994. Nature 368: 32-38. 2. Margolis, B. et al. 1992. Proc. Natl. Acad. Sci. 89: 8894-8898. 3. Ooi, J. et al. 1995. Oncogene 10: 1621-1630. 4. Stein, D. et al. 1994. EMBO J. 13: 1331-1340. 5. Hansen, H. et al. 1996. J. Biol. Chem. 271: 8882-8886. 6. Pawson, T. 1995. Nature 373: 573-580.