Serotonin signaling by maternal neurons upon stress ensures progeny survival

Abstract

19Germ cells are vulnerable to stress. Therefore, how organisms protect their future progeny from 20 damage in a fluctuating environment is a fundamental question in biology. We show that in 21Caenorhabditis elegans, serotonin released by maternal neurons during stress ensures the 22 viability and stress resilience of future offspring. Serotonin acts through a signal transduction 23 pathway conserved between C. elegans and mammalian cells to enable the transcription factor 24 HSF1 to alter chromatin in soon-to-be fertilized germ cells by recruiting the histone chaperone 25 FACT, displacing histones, and initiating protective gene expression. Without serotonin release 26 by maternal neurons, FACT is not recruited by HSF1 in germ cells, transcription occurs but is 27 delayed, and progeny of stressed C. elegans mothers fail to complete development. These 28 studies uncover a novel mechanism by which stress sensing by neurons is coupled to 29 transcription response times of germ cells to protect future offspring. 30 infection. Similarly, exposure to increasing temperatures enhances 5-HT release from the 54 serotonergic neurons (called NSM and ADF neurons) through the activity of the animal's 55 thermosensory neurons (called AFD neurons) and this release of 5-HT cell non-autonomously 56 protects the animal from proteotoxicity (Gracida, Dion, Harris, Zhang, & Calarco, 2017; Iwanir 57 et al., 2016; Shao et al., 2019; Tatum et al., 2015a). However, whether 5-HT released by the 58 parent upon the detection of stress protects germ cells and future progeny from stress is not 59 known. In fact, mammalian studies are suggestive of the opposite role for elevated levels of 5-60HT that accompany chronic stress in the parent, and increased 5-HT is thought to contribute to 61 behavioral and psychiatric disorders such as schizophrenia, depression, and autism in progeny 62through as yet poorly understood mechanisms (Bonnin et al.unexpected 64 effect given that stress-induced release of 5-HT by neurons and other 5-HT synthesizing cells is 65 a highly conserved phenomenon. 66 67Here we asked whether the stress-induced release of 5-HT by maternal neurons provides any 68 benefits to germ cells and the development of future progeny. We used C. elegans to address this 69 question in an in vivo setting, and cultured mammalian cells to dissect the molecular pathways by 70 which 5-HT might act and to examine the extent to which 5-HT mediated effects are conserved. 71We show that in C. elegans, 5-HT released by maternal neurons upon stress allows the 72 transcription factor heat shock factor 1 (HSF1) to shorten the time to onset of mRNA production 73 in soon-to-be fertilized germ cells. Specifically, 5-HT promotes the post-translational 74 modification of HSF1 by protein kinase A (PKA) allowing HSF1 to recruit the histone chaperone 75 FACT (FAcilitates Chromatin Transcription) and alter histone dynamics to initiate transcription. 76 5 This timely activation of HSF1 in germ cells ensures their viability and future stress tolerance: 77 embry...

What can a worm learn in a bacteria-rich habitat?

“…Interestingly, pathogenic bacteria are not the only environmental conditions that impact the worm for multiple generations. It has been shown that parental experiences, including dietary restriction, osmotic stress, temperature changes, olfactory imprinting, and prolonged starvation, can regulate the physiology of the offspring, some of which last for several generations and are mediated by small RNA pathways (Burton et al, 2017;Das et al, 2020;Demoinet, Li, & Roy, 2017;Greer et al, 2011;Hibshman, Hung, & Baugh, 2016;Jobson et al, 2015;Klosin, Casas, Hidalgo-Carcedo, Vavouri, & Lehner, 2017;Ni et al, 2016;Palominos et al, 2017;Posner et al, 2019;Rechavi et al, 2014;Remy, 2010;Schott, Yanai, & Hunter, 2014). These studies together show that C. elegans has evolved diverse adaptive strategies to generate long-term plasticity that lasts for multiple generations.…”

First Virtual International Congress on Cellular and Organismal Stress Responses, November 5–6, 2020

“…Finally, she discussed her recent findings that serotonin acts through a signal transduction pathway conserved between C. elegans and mammalian cells to enable the transcription factor HSF1 to alter chromatin in soon-to-be fertilized germ cells by recruiting the histone chaperone FACT, displacing histones, and initiating protective gene expression. Without serotonin release by maternal neurons, FACT is not recruited by HSF1 in germ cells and progeny of stressed C. elegans mothers fail to complete development (Das et al 2020). These studies are just beginning to uncover how stress sensing by maternal neurons, coupled to HSF1-dependent transcription in the germline, could result in the epigenetic remodeling of offspring (Das et al 2020).…”

“…Without serotonin release by maternal neurons, FACT is not recruited by HSF1 in germ cells and progeny of stressed C. elegans mothers fail to complete development (Das et al 2020). These studies are just beginning to uncover how stress sensing by maternal neurons, coupled to HSF1-dependent transcription in the germline, could result in the epigenetic remodeling of offspring (Das et al 2020).…”

Germline activity of the heat shock factor HSF-1 programs the insulin-receptordaf-2inC. elegans

“…We then allowed these oocytes to complete maturation, undergo fertilization, and develop into adults at normal growth temperature of 20°C. To activate HSF-1 in the germline, we chose regimen of long heat exposure (30 minutes or 60 minutes to 34°C) that is typically used to activate HSF-1 throughout the animal (33)(34)(35)(36) and a shorter, 5-minute heat-shock at 34°C, which we have previously shown is sufficient to induce HSF-1 transcriptional activity (33).…”

“…These animals express a truncated HSF-1 protein lacking the transactivation domain, where HSF-1 binds constitutively to the promoter regions of its target genes in the absence of heat shock, but is deficient in heat-shock induced binding ( Fig. S3 C, D) and transcription (33). Progeny that developed from heat-shocked germ cell oocytes of hsf-1 (sy441) I animals also did not undergo early life programming and did not display enhanced stress resilience (Fig.…”