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Embryo integrity regulates maternal proteostasis and stress resilience.

ABSTRACT: The proteostasis network is regulated by transcellular communication to promote health and fitness in metazoans. In Caenorhabditis elegans, signals from the germline initiate the decline of proteostasis and repression of cell stress responses at reproductive maturity, indicating that commitment to reproduction is detrimental to somatic health. Here we show that proteostasis and stress resilience are also regulated by embryo-to-mother communication in reproductive adults. To identify genes that act directly in the reproductive system to regulate somatic proteostasis, we performed a tissue targeted genetic screen for germline modifiers of polyglutamine aggregation in muscle cells. We found that inhibiting the formation of the extracellular vitelline layer of the fertilized embryo inside the uterus suppresses aggregation, improves stress resilience in an HSF-1-dependent manner, and restores the heat-shock response in the somatic tissues of the parent. This pathway relies on DAF-16/FOXO activation in vulval tissues to maintain stress resilience in the mother, suggesting that the integrity of the embryo is monitored by the vulva to detect damage and initiate an organismal protective response. Our findings reveal a previously undescribed transcellular pathway that links the integrity of the developing progeny to proteostasis regulation in the parent.

SUBMITTER: Sala AJ

PROVIDER: S-EPMC7197353 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Embryo integrity regulates maternal proteostasis and stress resilience.

Sala Ambre J AJ Bott Laura C LC Brielmann Renee M RM Morimoto Richard I RI

Genes & development 20200326 9-10

The proteostasis network is regulated by transcellular communication to promote health and fitness in metazoans. In <i>Caenorhabditis elegans</i>, signals from the germline initiate the decline of proteostasis and repression of cell stress responses at reproductive maturity, indicating that commitment to reproduction is detrimental to somatic health. Here we show that proteostasis and stress resilience are also regulated by embryo-to-mother communication in reproductive adults. To identify genes ...[more]

PMID: 32217667

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Project description:Early life stress (ELS) leads to a permanent reprogramming of biochemical stress response cascades that may also be relevant for the processing of chronic pain states such as neuropathy. Despite clinical evidence, little is known about ELS-related vulnerability for neuropathic pain and the possibly underlying etiology. In the framework of experimental studies aimed at investigating the respective relationships we used the established ELS model of maternal separation (MS). Rat dams and neonates were separated for 3 h/day from post-natal day 2-12. At adulthood, noxious mechanical and thermal thresholds were assessed before and during induction of neuropathic pain by chronic constriction injury (CCI). The potential involvement of spinal glutamatergic transmission, glial cells, pro-inflammatory cytokines and growth factors was studied by using qPCR. MS per se did not modify pain thresholds. But, when exposed to neuropathic pain, MS rats exhibited a marked reduction of thermal sensitivity and a delayed development of mechanical allodynia/hyperalgesia when compared to control animals. Also, MS did not alter glucocorticoid receptor mRNA levels, but prevented the CCI-induced down-regulation of NR1 and NR2 sub-units of the NMDA receptor and of the glutamate transporter EAAT3 as observed at 21 days post-surgery. Additionally, CCI-provoked up-regulation of glial cell markers was either prevented (GFAP for astrocytes) or dampened (Iba1 for microglia) by MS. Pro-inflammatory cytokine mRNA expression was either not affected (IL-6) or reduced (IL-1?) by MS shortly after CCI. The growth factors GDNF and NGF were only slightly downregulated 4 days after CCI in the MS-treated animals. The changes in glutamatergic signaling, astroglial and cytokine activation as well as neurotrophin expression could, to some extent, explain these changes in pain behavior. Taken together, the results obtained in the described experimental conditions support the mismatch theory of chronic stress where an early life stress, rather than predisposing individuals to certain pathologies, renders them resilient.

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Embryo integrity regulates maternal proteostasis and stress resilience.

Publications

Embryo integrity regulates maternal proteostasis and stress resilience.

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