Prolonged quiescence delays somatic stem cell-like division inCaenorhabditis elegansand is controlled by insulin signalling

Abstract

Cells can enter quiescence in adverse conditions and resume proliferation when the environment becomes favorable. Prolonged quiescence comes with a cost, reducing the subsequent speed and potential to return to proliferation. Here, we show that a similar process happens during Caenorhabditis elegans development, providing an in vivo model to study proliferative capacity after quiescence. Hatching under starvation provokes the arrest of blast cell divisions that normally take place during the first larval stage (L1). We have used a novel method to precisely quantify each stage of postembryonic development to analyze the consequences of prolonged L1 quiescence. We report that prolonged L1 quiescence delays the reactivation of blast cell divisions in C. elegans, leading to a delay in the initiation of postembryonic development. The transcription factor DAF‐16/FOXO is necessary for rapid recovery after extended arrest, and this effect is independent from its role as a suppressor of cell proliferation. Instead, the activation of DAF‐16 by decreased insulin signaling reduces the rate of L1 aging, increasing proliferative potential. We also show that yolk provisioning affects the proliferative potential after L1 arrest modulating the rate of L1 aging, providing a possible mechanistic link between insulin signaling and the maintenance of proliferative potential. Furthermore, variable yolk provisioning in embryos is one of the sources of interindividual variability in recovery after quiescence of genetically identical animals. Our results support the relevance of L1 arrest as an in vivo model to study stem cell‐like aging and the mechanisms for maintenance of proliferation potential after quiescence.

Vitellogenins - Yolk Gene Function and Regulation in Caenorhabditis elegans

“…Worms hatched from vitellogenin-depleted embryos, achieved by maternal knockdown of either vitellogenins or rme-2 , show an increased frequency of these defects, including sterility, as do the progeny of young mothers (Perez et al, 2017; Jordan et al, 2019). Accordingly, progeny of young mothers, with reduced vitellogenin titers, showed premature signs of aging (Roux et al, 2016) during L1 starvation (Olmedo et al, 2018). Increased embryonic vitellogenin titers lead to reduced insulin-like signaling in progeny, which mediates the supression of germline defects after recovery from L1 starvation (Jordan et al, 2019) and may also explain the supression of aging in starved L1s.…”

“…Additionally, increased vitellogenin in the embryos of older mothers explains a shortening of the time taken to reach adulthood after hatching, even in the absence of starvation (Perez et al, 2017). It was shown that young maternal age and embryonic vitellogenin depletion by rme-2 RNAi led to delayed adulthood after feeding in previously-starved L1s not by accelerating the overall rate of development but specifically prolonging the time required to initiate development from the L1 stage (Olmedo et al, 2018). High levels of yolk provisioning thus improve offspring outcomes, in both favorable and unfavorable conditions.…”

Neuronal perception of the social environment generates an inherited memory that controls the development and generation time of C. elegans

“…A recent study found that the developmental delay arising after recovery from starvationinduced L1 arrest occurrs not due to a slowing of developmental rate, but rather due to a delay in the initiation of post-embryonic development upon feeding. 44 This led us to hypothesize that pheromone exposure in the parents may affect the relative timing of post-embryonic developmental initiation in progeny somatic or germline tissues, rather than their relative rate of development. Furthermore, this hypothesis could explain the intergenerational germline delay as a latent effect of maternal control over an early developmental event, whose effects manifest in progeny up to adulthood.…”

“…These results suggest that the delay observed is largely due to a delay in developmental initiation rather than a slowing of developmental rate. 44 The phenotypes of the first progeny hatching on a fresh plate, laid shortly after parents were transferred, resembled those of worms hatched on the used plate, suggesting that it was an intergenerational effect of parental environment, rather than the environment encountered upon hatching, that determined the phenotype of progeny (Figures S1C-S1F). To .…”

Mitochondrial genome recovery by ATFS-1 is essential for development following starvation

“…Previous studies demonstrated that starvation leads to a reduction of daf-2 -mediated signaling as DAF-16 activity is required for starvation survival as well as maintaining germline quiescence (Baugh and Sternberg, 2006; Hibshman et al, 2017). Furthermore, upon feeding, daf-2 transcription is reduced, and DAF-16 activity is necessary to promote growth and development (Chen and Baugh, 2014; Kaplan et al, 2019; Olmedo et al, 2020) suggestive of a more nuanced daf-2 regulation. We propose a model that the prolonged lack of food during L1 arrest leads to modest reduction of daf-2 signaling along with the gradual decline in mitochondrial activity while sustaining foraging, depletion of mtDNA, mitochondrial fragmentation and reduced respiration.…”