Autism NPCs from both idiopathic and CNV 16p11.2 deletion patients exhibit dysregulation of proliferation and mitogenic responses

Connacher, Robert J.; Williams, Madeline; Prem, S; Yeung, Percy Luk; Matteson, Paul G.; Mehta, Monal; Markov, Anna; Peng, Cynthia S.; Zhou, Xin; McDermott, Conor; Pang, Zhiping P.; Flax, Judy; Brzustowicz, Linda M.; Lu, Che-Wei; Millonig, James H.; DiCicco‐Bloom, Emanuel

doi:10.1016/j.stemcr.2022.06.007

Cited by 6 publications

(9 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The current reports on the effects of 16p11.2 deletion on cortical NPC proliferation are few and variable, leaving the effects of this CNV on the ventral telencephalon largely unexplored. Enhanced proliferation (Connacher et al, 2022, Pucilowska et al, 2015, no difference in NPC proliferation rates (Deshpande et al, 2017, Roth et al, 2020 or a reduction in NPC proliferation (Urresti et al, 2021), as observed in our ventral progenitors, have been reported, further highlighting the increased variability associated with this deletion.…”

Section: Variability As a Hallmark Of 16p112 Deletionsupporting

confidence: 64%

“…Studies in 16p11.2 mouse models and patient derived NPCs have demonstrated enhanced cortical progenitor proliferation (Pucilowska et al, 2015, (Connacher et al, 2022, whereas other studies utilising human iPSC-derived cortical NPCs showed no difference in NPC proliferation rates (Deshpande et al, 2017, Roth et al, 2020. Therefore, we investigated whether the deletion affects the cell cycle of ventral progenitors within the outer SOX2+ peripheral region of the organoids, since control organoids formed very few rosettes.…”

Section: P112 Deletion Organoids Exhibited Increased Cell Cycle Lengt...mentioning

confidence: 99%

See 1 more Smart Citation

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

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.

show abstract

Section: Variability As a Hallmark Of 16p112 Deletionsupporting

confidence: 64%

Section: P112 Deletion Organoids Exhibited Increased Cell Cycle Lengt...mentioning

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

“…The current reports on the effects of 16p11.2 deletion on cortical NPC proliferation are few and variable, leaving the effects of this CNV on the ventral telencephalon largely unexplored. Enhanced proliferation ( Connacher et al, 2022 ; Pucilowska et al, 2015 ), no difference in NPC proliferation rates ( Deshpande et al, 2017 ; Roth et al, 2020 ) or a reduction in NPC proliferation ( Urresti et al, 2021 ), as observed in our ventral progenitors, have been reported, further highlighting the increased variability associated with this deletion.…”

Section: Discussionsupporting

confidence: 49%

“…Studies in 16p11.2 mouse models and patient-derived NPCs have demonstrated enhanced cortical progenitor proliferation ( Pucilowska et al, 2015 ; Connacher et al, 2022 ), whereas other studies using human iPSC-derived cortical NPCs showed no difference in NPC proliferation rates ( Deshpande et al, 2017 ; Roth et al, 2020 ). Therefore, we investigated whether the deletion affects the cell cycle of ventral progenitors within the outer SOX2 + peripheral region of the organoids, as control organoids formed very few rosettes.…”

Section: Resultsmentioning

confidence: 94%

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

et al. 2023

View full text Add to dashboard Cite

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.

show abstract

“…Indeed, altered regulation of proliferation has been demonstrated to cause defects in the progenitors’ fate and, ultimately, neuronal development trajectories (Pilaz et al, 2016). In several cellular models of ASD, both hyper- and hypo-proliferation of neural progenitors have been documented (Connacher et al, 2022; Marchetto et al, 2017; Mowat et al, 2003; Zucco et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Deficiency of the Heterogeneous Nuclear Ribonucleoprotein U locus leads to delayed hindbrain neurogenesis

Mastropasqua

Oksanen

Soldini

et al. 2022

Preprint

View full text Add to dashboard Cite

Genetic variants affecting Heterogeneous Nuclear Ribonucleoprotein U (HNRNPU) have been identified in several neurodevelopmental disorders (NDDs); however, the role of HNRNPU in human neural development and NDDs remains to be studied. Here, we describe the molecular and cellular outcomes of HNRNPU deficiency during in vitro neural differentiation of isogenic and patient-derived neuroepithelial stem cells. We demonstrate that HNRNPU deficiency leads to chromatin remodeling of A/B compartments, and transcriptional rewiring, partly by impacting exon inclusion during mRNA processing. Genomic regions affected by the chromatin restructuring and host genes of exon usage differences show a strong enrichment for genes implicated in epilepsies, intellectual disability, and autism. Lastly, we show the effects of the molecular reorganization at the cellular level, where HNRNPU downregulation leads to altered neurogenesis and an increased fraction of neural progenitors marked in the maturing neuronal population. We conclude that HNRNPU deficiency is responsible for the delayed commitment of neural progenitors to neuronal maturation, ultimately leading to altered neurogenesis.

show abstract

Autism NPCs from both idiopathic and CNV 16p11.2 deletion patients exhibit dysregulation of proliferation and mitogenic responses

Cited by 6 publications

References 0 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

Deficiency of the Heterogeneous Nuclear Ribonucleoprotein U locus leads to delayed hindbrain neurogenesis

Contact Info

Product

Resources

About