Non-autonomous DAF-16/FOXO activity antagonizes age-related loss of C. elegans germline stem/progenitor cells

Qin, Zhao; Hubbard, E. Jane Albert

doi:10.1038/ncomms8107

Cited by 58 publications

(104 citation statements)

References 37 publications

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“…Mutation of the daf-2 insulin/IGF-1 receptor increases C. elegans lifespan [34] and delays reproductive senescence [35, 36] and gonad degeneration [20, 37]. One possibility is that daf-2(−) suppresses gonad degeneration by reducing PA. daf-2 mutants fall broadly into two classes: class 1, e.g.…”

Section: Resultsmentioning

confidence: 99%

“…These results imply that daf-2 mutant suppression of gonad disintegration involves a mechanism unrelated to PA, though reduction in PA could play a role in class 2 mutants such as daf-2(e1370) . One possibility is that this mechanism is related to the smaller age decrease in mitotic germ cell populations seen in daf-2 mutants [18, 37]. …”

Section: Resultsmentioning

confidence: 99%

“…By this view, declining GP and run-on of PA are primary and secondary causes of gonad degeneration. In daf-2 mutants age-related loss of germline progenitor cells is reduced in daf-2 mutants [18, 37]; thus, maintenance of GP production in later life could protect against gonad atrophy. The role of declining GP rate in gonadal senescence warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

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Run-on of germline apoptosis promotes gonad senescence inC. elegans

et al. 2016

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Aging (senescence) includes causal mechanisms (etiologies) of late-life disease, which remain poorly understood. According to the recently proposed hyperfunction theory, based on the older theory of antagonistic pleiotropy, senescent pathologies can arise from futile, post-reproductive run-on of processes that in early life promote fitness. Here we apply this idea to investigate the etiology of senescent pathologies in the reproductive system of Caenorhabditis elegans hermaphrodites, particularly distal gonad degeneration and disintegration. Hermaphrodite germ cells frequently undergo “physiological” (non-damage-induced) apoptosis (PA) to provision growing oocytes. Run-on of such PA is a potential cause of age-related gonad degeneration. We document the continuation of germline apoptosis in later life, and report that genetically blocking or increasing PA retards or accelerates degeneration, respectively. In wild-type males, which lack germ line apoptosis, gonad disintegration does not occur. However, mutational induction of PA in males does not lead to gonad disintegration. These results suggest that as germ-cell proliferation rate declines markedly in aging hermaphrodites (but not males), run-on of PA becomes a pathogenic mechanism that promotes gonad degeneration. This illustrates how hyperfunction, or non-adaptive run-on in later life of a process that promotes fitness in early life, can promote atrophic senescent pathology in C. elegans.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Run-on of germline apoptosis promotes gonad senescence inC. elegans

et al. 2016

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“…The first is adult reproductive diapause, where in response to total food deprivation the germline undergoes atrophy/autophagy of essentially all meiotic germ cells with only a proliferative zone with as few as 35 germ cells remaining; following return to food the distal-proximal germline gametogenesis pattern is reestablished rapidly and progeny are generated (Angelo and Van Gilst 2009;Seidel and Kimble 2011). The second is a recently described mechanism that maintains a relatively large proliferative zone to extend reproductive competence in mid-aged hermaphrodites that have exhausted their selfsperm (and presumably in females of related male/female nematodes species) in anticipation of progeny production following mating (Qin and Hubbard 2015). In response to mating, the germline needs to produce large numbers of meiotic prophase germ cells to generate oocytes and/or nurse cells for progeny production.…”

Section: Comparison To Other Stem Cell Systemsmentioning

confidence: 99%

Analysis of Germline Stem Cell Differentiation Following Loss of GLP-1 Notch Activity in Caenorhabditis elegans

Fox

Schedl

2015

Genetics

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Stem cells generate the differentiated progeny cells of adult tissues. Stem cells in the Caenorhabditis elegans hermaphrodite germline are maintained within a proliferative zone of 230 cells, 20 cell diameters in length, through GLP-1 Notch signaling. The distal tip cell caps the germline and supplies GLP-1-activating ligand, and the distal-most germ cells that occupy this niche are likely self-renewing stem cells with active GLP-1 signaling. As germ cells are displaced from the niche, GLP-1 activity likely decreases, yet mitotically cycling germ cells are found throughout the proliferative zone prior to overt meiotic differentiation. Following loss of GLP-1 activity, it remains unclear whether stem cells undergo transit-amplifying (TA) divisions or more directly enter meiosis. To distinguish between these possibilities we employed a temperature-sensitive (ts) glp-1 mutant to manipulate GLP-1 activity. We characterized proliferative zone dynamics in glp-1(ts) mutants at permissive temperature and then analyzed the kinetics of meiotic entry of proliferative zone cells after loss of GLP-1. We found that entry of proliferative zone cells into meiosis following loss of GLP-1 activity is largely synchronous and independent of their distal-proximal position. Furthermore, the majority of cells complete only a single mitotic division before entering meiosis, independent of their distal-proximal position. We conclude that germ cells do not undergo TA divisions following loss of GLP-1 activity. We present a model for the dynamics of the proliferative zone that utilizes cell cycle rate and proliferative zone size and output and incorporates the more direct meiotic differentiation of germ cells following loss of GLP-1 activity.

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“…These cells also intrinsically acquire changes during ageing, which lead to irreversible senescence in very old (geriatric) mice (Sousa-Victor et al, 2014). Stem cell population sizes also decline during ageing (López-Otín et al, 2013), and a recent study (Qin and Hubbard, 2015) provided evidence that the size of the GSC population in ageing C. elegans adults is nonautonomously controlled by IIS in the proximal somatic gonad, in a manner dependent on DAF-16, the C. elegans FOXO orthologue Lin et al, 2001). However, the kinetics of the decline in the GSC population, as well as the mechanisms that regulate stem cell proliferation rates during ageing remain unclear.…”

Section: Introductionmentioning

confidence: 99%

daf-18/PTEN locally antagonizes insulin signalling to couple germline stem cell proliferation to oocyte needs inC. elegans

2015

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During development, stem cell populations rapidly proliferate to populate the expanding tissues and organs. During this phase, nutrient status, by systemically affecting insulin/IGF-1 signalling, largely dictates stem cell proliferation rates. In adults, however, differentiated stem cell progeny requirements are generally reduced and vary according to the spatiotemporal needs of each tissue. We demonstrate here that differential regulation of germline stem cell proliferation rates in Caenorhabditis elegans adults is accomplished through localized neutralization of insulin/IGF-1 signalling, requiring DAF-18/PTEN, but not DAF-16/FOXO. Indeed, the specific accumulation of oocytes, the terminally differentiated stem cell progeny, triggers a feedback signal that locally antagonizes insulin/ IGF-1 signalling outputs in the germ line, regardless of their systemic levels, to block germline stem cell proliferation. Thus, during adulthood, stem cells can differentially respond within tissues to otherwise equal insulin/IGF-1 signalling inputs, according to the needs for production of their immediate terminally differentiated progeny.

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Non-autonomous DAF-16/FOXO activity antagonizes age-related loss of C. elegans germline stem/progenitor cells

Cited by 58 publications

References 37 publications

Run-on of germline apoptosis promotes gonad senescence inC. elegans

Run-on of germline apoptosis promotes gonad senescence inC. elegans

Analysis of Germline Stem Cell Differentiation Following Loss of GLP-1 Notch Activity in Caenorhabditis elegans

daf-18/PTEN locally antagonizes insulin signalling to couple germline stem cell proliferation to oocyte needs inC. elegans

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