Nutrient restriction causes reversible G2 arrest in <i>Xenopus</i> neural progenitors

McKeown, Caroline R.; Cline, Hollis T.

doi:10.1242/dev.178871

Cited by 13 publications

(9 citation statements)

References 103 publications

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“…Cell cycle delay is further supported by the observation that contrary to overall Sox2 positive cell number, the number of transfected, Sox2-positive cells in chicken embryos was increased relative to controls. In agreement with our findings, nutrient restriction was shown to arrest the proliferation of neural progenitors of Xenopus larvae and zebrafish reversibly in G2, suggesting that most of the cells were quiescent( 32 ). While arrest did not require mTOR signaling, nutrient dependent cell cycle reentry was mTOR dependent.…”

Section: Discussionsupporting

confidence: 92%

SAICAr-dependent and independent effects of ADSL deficiency on neurodevelopment

Dutto

Gerhards

Herrera

et al. 2020

Preprint

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Adenylosuccinate Lyase (ADSL) functions in the de novo purine biosynthesis pathway. ADSL deficiency (ADSLD) causes numerous neurodevelopmental pathologies, including microcephaly and autism spectrum disorder. ADSLD patients have normal purine nucleotide levels but exhibit accumulation of the dephosphorylated ADSL substrates SAICAr and S-Ado. SAICAr was implicated in the neurotoxic effects of ADSLD, although its role remains unknown. We examined the effects of ADSL depletion in human cells and found increased DNA damage signaling, that was rescued by nucleosides, and impaired primary ciliogenesis, that was rescued by reducing SAICAr. By analyzing ADSL deficient chicken and zebrafish embryos we observed impaired neurogenesis and microcephaly, and neuroprogenitor attrition in zebrafish was rescued by reducing SAICAr. Zebrafish embryos also displayed phenotypes commonly linked to ciliopathies. Our results suggest that both reduced purine levels and SAICAr accumulation contribute to neurodevelopmental pathology in ADSLD and defective ciliogenesis may influence the ADSLD phenotypic spectrum.

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Section: Discussionsupporting

confidence: 92%

SAICAr-dependent and independent effects of ADSL deficiency on neurodevelopment

Dutto

Gerhards

Herrera

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Cell cycle delay was further supported by the observation that, contrary to overall Sox2 positive cell numbers, the number of transfected, Sox2-positive cells in chicken embryos was increased relative to controls. In agreement with our findings, nutrient restriction was shown to arrest the proliferation of neural progenitors of Xenopus larvae and zebrafish reversibly in G2, suggesting that most of the cells were quiescent (43), consistent with the lack of evidence for cell death or senescence in ADSL depleted systems. While arrest in Xenopus progenitors did not require mTOR signaling, nutrient dependent cell cycle reentry was mTOR dependent.…”

Section: Discussionsupporting

confidence: 92%

Pathway-specific effects of ADSL deficiency on neurodevelopment

Dutto

Gerhards

Herrera

et al. 2022

eLife

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Adenylosuccinate Lyase (ADSL) functions in de novo purine biosynthesis (DNPS) and the purine nucleotide cycle. ADSL deficiency (ADSLD) causes numerous neurodevelopmental pathologies, including microcephaly and autism spectrum disorder. ADSLD patients have normal serum purine nucleotide levels but exhibit accumulation of dephosphorylated ADSL substrates, S-Ado and SAICAr, the latter being implicated in neurotoxic effects through unknown mechanisms. We examined the phenotypic effects of ADSL depletion in human cells and their relation to phenotypic outcomes. Using specific interventions to compensate for reduced purine levels or modulate SAICAr accumulation, we found that diminished AMP levels resulted in increased DNA damage signaling and cell cycle delays, while primary ciliogenesis was impaired specifically by loss of ADSL or administration of SAICAr. ADSL deficient chicken and zebrafish embryos displayed impaired neurogenesis and microcephaly. Neuroprogenitor attrition in zebrafish embryos was rescued by pharmacological inhibition of DNPS, but not increased nucleotide concentration. Zebrafish also displayed phenotypes commonly linked to ciliopathies. Our results suggest that both reduced purine levels and impaired DNPS contribute to neurodevelopmental pathology in ADSLD and that defective ciliogenesis may influence the ADSLD phenotypic spectrum.

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“…Pedersen, 1970). Recent studies in Drosophila , Xenopus Laevis and C. elegans tissues uncovered that populations of adult stem cells are halted in G2-phase and can be triggered to divide by growth factor and nutrient signaling (McKeown and Cline, 2019; Morris and Spradling, 2011; Otsuki and Brand, 2018; Seidel and Kimble, 2015; Zielke et al, 2014). Extrinsic control of G2/M progression may thus be a widely conserved element of the eukaryotic cell cycle.…”

Section: Discussionmentioning

confidence: 99%

“…The division rate of these cells is presumed to be independent of external regulation, as it has been a prevailing dogma that following G1/S transition, progression through the cell cycle becomes irresponsive to extrinsic cues (Pardee, 1989). However, recent findings in invertebrate germline and neural stem cells revealed that progression through later cell cycle stages can be modulated by nutrient signaling (McKeown and Cline, 2019; Otsuki and Brand, 2018; Seidel and Kimble, 2015). Yet, how extrinsic signals influence progression through later stages of the cell cycle and thereby the rate of cell division in epithelia is not well understood.…”

Section: Introductionmentioning

confidence: 99%

A mechanical G2 checkpoint controls epithelial cell division through E-cadherin-mediated regulation of Wee1-Cdk1

Donker

Vliem

Canever

et al. 2021

Preprint

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Epithelial cell divisions must be tightly coordinated with cell loss to preserve epithelial integrity. However, it is not well understood how the rate of epithelial cell division adapts to changes in cell number, for instance during homeostatic turnover or upon wounding of epithelia. Here, we show epithelial cells sense local cell density through mechanosensitive E-cadherin adhesions to control G2/M cell cycle progression. We demonstrate that tensile forces on E-cadherin adhesions are reduced as local cell density increases, which prompts the accumulation of the G2 checkpoint kinase Wee1. This elevated abundance of Wee1 results in inhibitory phoshorylation of Cdk1, and thereby establishes a pool of cells that is temporarily halted in G2-phase. Importantly, these cells are readily triggered to divide upon epithelial wounding, due to the consequent increase in intercellular forces and resulting degradation of Wee1. Our data thus demonstrate that epithelial cell division is controlled by a mechanical G2 checkpoint, which is regulated by cell density-dependent intercellular forces sensed and transduced by E-cadherin adhesions.

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Nutrient restriction causes reversible G2 arrest in Xenopus neural progenitors

Cited by 13 publications

References 103 publications

SAICAr-dependent and independent effects of ADSL deficiency on neurodevelopment

SAICAr-dependent and independent effects of ADSL deficiency on neurodevelopment

Pathway-specific effects of ADSL deficiency on neurodevelopment

A mechanical G2 checkpoint controls epithelial cell division through E-cadherin-mediated regulation of Wee1-Cdk1

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