G1 Phase Lengthening During Neural Tissue Development Involves CDC25B Induced G1 Heterogeneity

Delgado, Angie Molina; Frédéric, Bonnet; Lobjois, Valérie; Bel-Vialar, Sophie; Gautrais, Jacques; Pituello, Fabienne; Agius, Eric

doi:10.1101/2020.11.06.370833

Cited by 3 publications

(5 citation statements)

References 59 publications

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“…Subsequently, at stages when telencephalic organoids start to organise their neural cells into rosettes in a process that resembles the development of the neuroepithelium of the neural tube, deletion organoids showed, on average, increased rosette formation. This increased state of organisation coincided with higher densities of COUPTFII expressing cells and longer cell cycles (Wilcock et al, 2007, Molina et al, 2020). As with the growth rates recorded at earlier stages, the relative rosette area, COUPTFII density and the duration of G1 and G2M phases varied more in deletion organoids than in controls.…”

Section: Discussionmentioning

confidence: 84%

“…Because cell cycle and G1-phase lengthening are features of neural stem cells undergoing neurogenic cell divisions (Wilcock et al, 2007, Molina et al, 2020), we investigated whether this may affect progenitor differentiation in deletion organoids. We performed an additional study to generate one batch of ventral organoids from the parent line (GM8) and the deletion line (DELB8) containing 4-6 organoids per line.…”

Section: Resultsmentioning

confidence: 99%

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16p11.2 locus decelerates subpallial maturation and limits variability in human iPSC-derived ventral telencephalic organoids

Fetit

Theil

Pratt

et al. 2022

Preprint

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Inhibitory interneurons regulate the activity of cortical circuitry, and their dysfunction has been implicated in Autism Spectrum Disorder (ASD). 16p11.2 microdeletions are genetically linked to 1% of ASD. However, there have been few studies of the effects of this microdeletion on interneuron development. Using ventral telencephalic organoids derived from human induced pluripotent stem cells, we investigated the effect of this microdeletion on organoid size, progenitor proliferation and organisation into neural rosettes, ganglionic eminence (GE) marker expression at early developmental timepoints and expression of the neuronal marker, NEUN at later stages. Early deletion organoids exhibited significantly greater variations in size with concomitant increases in relative neural rosette area and the expression of the ventral telencephalic marker, COUPTFII, with significantly increased variability in these properties. Cell cycle analysis revealed a significant increase in total cell cycle length caused primarily by an elongated G1-phase, the duration of which also varied significantly more than normal. Late deletion organoids increased their expression of the neuronal marker NEUN. We propose that 16p11.2 microdeletions increase developmental variability and may contribute to ASD aetiology by lengthening the cell cycle of ventral progenitors, promoting premature differentiation into interneurons.

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Section: Discussionmentioning

confidence: 84%

Section: Resultsmentioning

confidence: 99%

16p11.2 locus decelerates subpallial maturation and limits variability in human iPSC-derived ventral telencephalic organoids

Fetit

Theil

Pratt

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Subsequently, at stages when telencephalic organoids start to organise their neural cells into rosettes in a process that resembles the development of the neuroepithelium of the neural tube, deletion organoids showed, on average, increased rosette formation. This increased state of organisation coincided with higher densities of COUPTFII-expressing cells and longer cell cycles ( Wilcock et al, 2007 ; Molina et al, 2020 preprint). As with the growth rates recorded at earlier stages, the relative rosette area, COUPTFII density, and the duration of G1 and G2M phases varied more in deletion organoids than in controls.…”

Section: Discussionmentioning

confidence: 92%

“…Because cell cycle and G1-phase lengthening are features of neural stem cells undergoing neurogenic cell divisions ( Wilcock et al, 2007 ; Molina et al, 2020 preprint), we investigated whether this may affect progenitor differentiation in deletion organoids. The mean fluorescence intensity of TUJ1 and the GABAergic interneuron marker GAD67 were quantified relative to organoid size at days 33-35 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

16p11.2 deletion accelerates subpallial maturation and increases variability in human iPSC-derived ventral telencephalic organoids

et al. 2023

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Inhibitory interneurons regulate cortical circuit activity, and their dysfunction has been implicated in autism spectrum disorder (ASD). 16p11.2 microdeletions are genetically linked to 1% of ASD cases. However, few studies investigate the effects of this microdeletion on interneuron development. Using ventral telencephalic organoids derived from human induced pluripotent stem cells, we have investigated the effect of this microdeletion on organoid size, progenitor proliferation and organisation into neural rosettes, ganglionic eminence marker expression at early developmental timepoints, and expression of the neuronal marker NEUN at later stages. At early stages, deletion organoids exhibited greater variations in size with concomitant increases in relative neural rosette area and the expression of the ventral telencephalic marker COUPTFII, with increased variability in these properties. Cell cycle analysis revealed an increase in total cell cycle length caused primarily by an elongated G1 phase, the duration of which also varied more than normal. At later stages, deletion organoids increased their NEUN expression. We propose that 16p11.2 microdeletions increase developmental variability and may contribute to ASD aetiology by lengthening the cell cycle of ventral progenitors, promoting premature differentiation into interneurons.

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“…However, how exactly cells are able to "keep time" to reliably lengthen their cell cycle remains unclear. A recent preprint by Molina et al [2020] reports that, in the chick spinal cord, rather than specific and coordinated lengthening of individual progenitors, the overall lengthening of the cell cycle at a population level occurs due to an increased heterogeneity of cell cycle length over time [Molina et al, 2020]. The authors compare this finding to work done in epidermal stem cells, where heterogeneity of cell cycle length is linked to the heterogeneity of cell growth [Xie and Skotheim, 2020].…”

Section: Cell Cyclementioning

confidence: 99%

Timing as a Mechanism of Development and Evolution in the Cerebral Cortex

Fenlon

2021

Brain Behav Evol

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One of the biggest mysteries in neurobiology concerns the mechanisms responsible for the diversification of the brain over different time scales i.e. during development and evolution. Subtle differences in the timing of biological processes during development, e.g. onset, offset, duration, speed and sequence, can trigger large changes in phenotypic outcomes. At the level of a single organism, altered timing of developmental events can lead to individual variability, as well as malformation and disease. At the level of phylogeny, there are known interspecies differences in the timing of developmental events, and this is thought to be an important factor that drives phenotypic variation across evolution, known as heterochrony. A particularly striking example of phenotypic variation is the evolution of human cognitive abilities, which has largely been attributed to the development of the mammalian-specific neocortex and its subsequent expansion in higher primates. Here, I review how the timing of different aspects of cortical development specifies developmental outcomes within species, including processes of cell proliferation and differentiation, neuronal migration and lamination, and axonal targeting and circuit maturation. Some examples of the ways that different processes might “keep time” in the cortex are explored, reviewing potential cell-intrinsic and -extrinsic mechanisms. Further, by combining this knowledge with known differences in timing across species, timing changes that may have occurred during evolution are identified, which perhaps drove the phylogenetic diversification of neocortical structure and function.

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G1 Phase Lengthening During Neural Tissue Development Involves CDC25B Induced G1 Heterogeneity

Cited by 3 publications

References 59 publications

16p11.2 locus decelerates subpallial maturation and limits variability in human iPSC-derived ventral telencephalic organoids

16p11.2 locus decelerates subpallial maturation and limits variability in human iPSC-derived ventral telencephalic organoids

16p11.2 deletion accelerates subpallial maturation and increases variability in human iPSC-derived ventral telencephalic organoids

Timing as a Mechanism of Development and Evolution in the Cerebral Cortex

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