Retinoblastoma protein controls growth, survival and neuronal migration in human cerebral organoids

Matsui, Takeshi K.; Nieto-Esteìvez, Vanesa; Kyrychenko, Sergii; Schneider, Jay W.; Hsieh, Jenny

doi:10.1242/jcs.203984

Cited by 8 publications

(8 citation statements)

References 23 publications

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“…Comparing the behaviour of Pax6+ and Pax6-cells in the same organoid has the significant advantage of removing potential confounding effects of variation in cell behaviour between different clonal ES cell lines or organoid batches. Loss of Pax6 had no effect on the proportion of actively proliferating cells in the organoids which was similar to the proportion of proliferating cells reported in human cerebral organoids (Matsui et al ., 2017).…”

Section: Discussionsupporting

confidence: 88%

Pax6 mutant cerebral organoids partially recapitulate phenotypes of Pax6 mutant mouse strains

Ferdaos

Lowell

Mason

2022

Preprint

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Cerebral organoids show great promise as tools to unravel the complex mechanisms by which the mammalian brain develops during embryogenesis. We generated mouse cerebral organoids harbouring constitutive or conditional mutations in Pax6, which encodes a transcription factor with multiple important roles in brain development. By comparing the phenotypes of mutant organoids with the well-described phenotypes of Pax6 mutant mouse embryos, we evaluated the extent to which cerebral organoids reproduce phenotypes previously described in vivo. Organoids lacking Pax6 showed multiple phenotypes associated with its activity in mice, including precocious neural differentiation, altered cell cycle and an increase in abventricular mitoses. Neural progenitors in both Pax6 mutant and wild type control organoids cycled more slowly than their in vivo counterparts, but nonetheless we were able to identify clear changes to cell cycle attributable to the absence of Pax6. Our findings support the value of cerebral organoids as tools to explore mechanisms of brain development, complementing the use of mouse models.

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Section: Discussionsupporting

confidence: 88%

Pax6 mutant cerebral organoids partially recapitulate phenotypes of Pax6 mutant mouse strains

Ferdaos

Lowell

Mason

2022

Preprint

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“…(chromatin remodeling via histone deacetylation (52,53) including in response to drugs of abuse(54)), and RB1 (cell survival and migration (55)).…”

Section: Enrichment Of Differentially Expressed Transcripts Involved mentioning

confidence: 99%

Transcriptional alterations in opioid use disorder reveal an interplay between neuroinflammation and synaptic remodeling

Seney

Moon-Kim

Glausier

et al. 2020

Preprint

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Prevalence rates of opioid use disorder (OUD) have increased dramatically, accompanied by a surge of overdose deaths. While opioid dependence has been extensively studied in preclinical models, we still have a very limited understanding of the biological changes that occur in the brains of people who chronically use opioids and who are diagnosed with OUD. To address this, we conducted the largest transcriptomics study to date using postmortem brains from subjects with OUD. We focused on the dorsolateral prefrontal cortex (DLPFC) and nucleus accumbens (NAc), two regions heavily implicated in OUD. We discovered a high degree of overlap in transcripts between DLPFC and NAc in OUD, primarily associated with neuroinflammation. Moreover, additional transcripts were enriched for factors that control pro-inflammatory cytokine-mediated signaling and remodeling of the extracellular matrix (ECM). Our results also implicate a role for microglia as a critical driver for opioid-induced neuroplasticity. Overall, our findings reveal new connections between the brain’s immune system and opioid dependence in the human brain.

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“…In terms of potential mediators, 5 out of 12 DMPs with a significant mediation effect (ACME and total effect) were mapped to genes involved in neuron functions and some associated to neurodevelopmental disorders: MYOM2 (cg08174789), RB1 (cg13389575), C10orf118 (cg05405872), STXBP6 (cg11734401), and TOR1AIP2 (cg07761912) . [37][38][39] C10orf118 and STXBP6 are involved with vesicle trafficking and signaling 40 and are associated with dendritic protein localization in neurons. 41 TOR1AIP1 encodes cofactors for the ATPase TorsinA, important to maintain developing neurons, during neuronal differentiation.…”

Section: Discussionmentioning

confidence: 99%

DNA methylation mediates a randomized controlled trial home-visiting intervention during pregnancy and the Bayley infant’s cognitive scores at 12 months of age

Euclydes

Gastaldi

Feltrin

et al. 2022

J Dev Orig Health Dis

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The crosstalk between maternal stress exposure and fetal development may be mediated by epigenetic mechanisms, including DNA methylation (DNAm). To address this matter, we collect 32 cord blood samples from low-income Brazilian pregnant adolescents participants of a pilot randomized clinical intervention study (ClinicalTrials.gov, Identifier: NCT02807818). We hypothesized that the association between the intervention and infant neurodevelopmental outcomes at 12 months of age would be mediated by DNAm. First, we searched genome methylation differences between cases and controls using different approaches, as well as differences in age acceleration (AA), represented by the difference of methylation age and birth age. According to an adjusted p-value ≤ 0.05 we identified 3090 differentially methylated positions- CpG sites (DMPs), 21 differentially methylated regions (DMRs) and one comethylated module weakly preserved between groups. The intervention group presented a smaller AA compared to the control group (p = 0.025). A logistic regression controlled by sex and with gestational age indicated a coefficient of −0.35 towards intervention group (p = 0.016) considering AA. A higher cognitive domain score from Bayley III scale was observed in the intervention group at 12 months of age. Then, we performed a potential causal mediation analysis selecting only DMPs highly associated with the cognitive domain (adj. R2 > 0.4), DMRs and CpGs of hub genes from the weakly preserved comethylated module and epigenetic clock as raw values. DMPs in STXBP6, and PF4 DMR, mediated the association between the maternal intervention and the cognitive domain at 12 months of age. In conclusion, DNAm in different sites and regions mediated the association between intervention and cognitive outcome.

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Retinoblastoma protein controls growth, survival and neuronal migration in human cerebral organoids

Cited by 8 publications

References 23 publications

Pax6 mutant cerebral organoids partially recapitulate phenotypes of Pax6 mutant mouse strains

Pax6 mutant cerebral organoids partially recapitulate phenotypes of Pax6 mutant mouse strains

Transcriptional alterations in opioid use disorder reveal an interplay between neuroinflammation and synaptic remodeling

DNA methylation mediates a randomized controlled trial home-visiting intervention during pregnancy and the Bayley infant’s cognitive scores at 12 months of age

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