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

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

doi:10.1016/j.stemcr.2022.04.019

Cited by 16 publications

(17 citation statements)

References 63 publications

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“…Indeed, many 16p11.2 transcripts are expressed by IN progenitors in the GE [ 46 , 66 , 84 ]. Studies on other types of NPC, both rodent cortical NPCs destined to become ExNs and hIPSC derived NPCs, show that the 16p11.2 microdeletion affects processes including gene expression, proliferation, and cell migration that occur before INs reach the cerebral cortex [ 19 , 55 , 56 , 65 , 76 ]. Overall it seems likely that the phenotypes of postnatal 16p11.2 ± INs may result in part from cumulative perturbations along their developmental trajectory although testing this hypothesis is well beyond the scope of the current study.…”

Section: Discussionmentioning

confidence: 99%

“…Perhaps unsurprisingly given the genetic and symptomatic complexity of 16p11.2 syndrome, studies using human and animal models have identified diverse 16p11.2 neuronal phenotypes at various stages of development including differential gene expression, proliferation, signalling, cell and tissue anatomy, electrophysiology, and behaviour [ 1 , 2 , 6 , 9 , 19 , 22 , 35 , 45 , 55 , 56 , 59 , 60 , 65 , 70 , 76 ]. The 16p11.2 locus spans 27 protein coding genes each of which is a potential risk factor for the facets of 16p11.2 syndrome.…”

Section: Introductionmentioning

confidence: 99%

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Identifying foetal forebrain interneurons as a target for monogenic autism risk factors and the polygenic 16p11.2 microdeletion

et al. 2023

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Background Autism spectrum condition or ‘autism’ is associated with numerous genetic risk factors including the polygenic 16p11.2 microdeletion. The balance between excitatory and inhibitory neurons in the cerebral cortex is hypothesised to be critical for the aetiology of autism making improved understanding of how risk factors impact on the development of these cells an important area of research. In the current study we aim to combine bioinformatics analysis of human foetal cerebral cortex gene expression data with anatomical and electrophysiological analysis of a 16p11.2+/- rat model to investigate how genetic risk factors impact on inhibitory neuron development. Methods We performed bioinformatics analysis of single cell transcriptomes from gestational week (GW) 8–26 human foetal prefrontal cortex and anatomical and electrophysiological analysis of 16p11.2+/- rat cerebral cortex and hippocampus at post-natal day (P) 21. Results We identified a subset of human interneurons (INs) first appearing at GW23 with enriched expression of a large fraction of risk factor transcripts including those expressed from the 16p11.2 locus. This suggests the hypothesis that these foetal INs are vulnerable to mutations causing autism. We investigated this in a rat model of the 16p11.2 microdeletion. We found no change in the numbers or position of either excitatory or inhibitory neurons in the somatosensory cortex or CA1 of 16p11.2+/- rats but found that CA1 Sst INs were hyperexcitable with an enlarged axon initial segment, which was not the case for CA1 pyramidal cells. Limitations The human foetal gene expression data was acquired from cerebral cortex between gestational week (GW) 8 to 26. We cannot draw inferences about potential vulnerabilities to genetic autism risk factors for cells not present in the developing cerebral cortex at these stages. The analysis 16p11.2+/- rat phenotypes reported in the current study was restricted to 3-week old (P21) animals around the time of weaning and to a single interneuron cell-type while in human 16p11.2 microdeletion carriers symptoms likely involve multiple cell types and manifest in the first few years of life and on into adulthood. Conclusions We have identified developing interneurons in human foetal cerebral cortex as potentially vulnerable to monogenic autism risk factors and the 16p11.2 microdeletion and report interneuron phenotypes in post-natal 16p11.2+/- rats.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identifying foetal forebrain interneurons as a target for monogenic autism risk factors and the polygenic 16p11.2 microdeletion

et al. 2023

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“…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%

“…Indeed, altered regulation of proliferation has been demonstrated to cause defects in the progenitors’ fate and, ultimately, neuronal development trajectories (Lalli et al, 2020; Pilaz et al, 2016). In several cellular models of ASD, unbalanced neural progenitors population due to both hyper- and hypo-proliferation of the progenitors have been documented (Connacher et al, 2022; Marchetto et al, 2017; Mowat et al, 2003; Zucco et al, 2018). Accordingly, we hypothesize that the observed downregulation of the synaptic and neuronal maturation markers is due to abnormal enrichment of progenitor at D28 stage and a consequence of the delayed maturation process.…”

Section: Discussionmentioning

confidence: 99%

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

Mastropasqua

Oksanen

Soldini

et al. 2022

Preprint

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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.

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“…Many studies, including ours, have used patient‐derived iPSCs with various genetic variants 37–44 . The addition of iPSCs to other approaches has widened the molecular and cellular phenotypes owing to genetic variants in humans.…”

Section: Attempt To Understand the Genetic‐based Latent Pathogenesis ...mentioning

confidence: 99%

Shedding light on latent pathogenesis and pathophysiology of mental disorders: The potential ofiPScell technology

Arioka

Okumura

Sakaguchi

et al. 2023

Psychiatry Clin Neurosci

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Mental disorders are considered as one of the major healthcare issues worldwide owing to their significant impact on the quality of life of patients, causing serious social burdens. However, it is hard to examine the living brain—a source of psychiatric symptoms—at the cellular, subcellular, and molecular levels, which poses difficulty in determining the pathogenesis and pathophysiology of mental disorders. Recently, induced pluripotent stem cell (iPSC) technology has been used as a novel tool for research on mental disorders. We believe that the iPSC‐based studies will address the limitations of other research approaches, such as human genome, postmortem brain study, brain imaging, and animal model analysis. Notably, studies using integrated iPSC technology with genetic information have provided significant novel findings to date. This review aimed to discuss the history, current trends, potential, and future of iPSC technology in the field of mental disorders. Although iPSC technology has several limitations, this technology can be used in combination with the other approaches to facilitate studies on mental disorders.

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

Cited by 16 publications

References 63 publications

Identifying foetal forebrain interneurons as a target for monogenic autism risk factors and the polygenic 16p11.2 microdeletion

Identifying foetal forebrain interneurons as a target for monogenic autism risk factors and the polygenic 16p11.2 microdeletion

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

Shedding light on latent pathogenesis and pathophysiology of mental disorders: The potential ofiPScell technology

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