MeCP2-regulated miRNAs control early human neurogenesis through differential effects on ERK and AKT signaling

Mellios, Nikolaos; Feldman, Danielle; Sheridan, Steven D.; Ip, Jacque Pak Kan; Kwok, Showming; Amoah, Stephen; Rosen, B.P.; Rodriguez, Brian A.; Crawford, Ben; Swaminathan, Radha; Chou, Stephanie; Li, Yun; Ziats, Mark N.; Ernst, Carl; Jaenisch, Rudolf; Haggarty, Stephen J.; Sur, Mriganka

doi:10.1038/mp.2017.86

Cited by 220 publications

(188 citation statements)

References 76 publications

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“…However, these changes likely present well before clinical symptoms. For example, a recent hiPSC-based study has suggested that Rett may impact prenatal neurogenesis through microRNA-mediated changes in AKT and ERK activity 26 . Interestingly, while neuroanatomical changes in dendritic arborization and spine density have been reported in multiple Rett models 25,[27][28][29][30] , gross structural abnormalities are less prevalent.…”

Section: Rett Syndrome Fusion Organoids Exhibit Hypersynchronous Neurmentioning

confidence: 99%

Identification of neural oscillations and epileptiform changes in human brain organoids

Samarasinghe

Miranda

Buth

et al. 2019

Preprint

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Human brain organoids represent a powerful tool for the study of human neurological diseases particularly those that impact brain growth and structure. However, many neurological diseases lack obvious anatomical abnormalities, yet significantly impact neural network functions, raising the question of whether organoids possess sufficient neural network architecture and complexity to model these conditions. Here, we explore the network level functions of brain organoids using calcium sensor imaging and extracellular recording approaches that together reveal the existence of complex oscillatory network behaviors reminiscent of intact brain preparations. We further demonstrate strikingly abnormal epileptiform network activity in organoids derived from a Rett Syndrome patient despite only modest anatomical differences from isogenically matched controls, and rescue with an unconventional neuromodulatory drug Pifithrin-a. Together, these findings provide an essential foundation for the utilization of human brain organoids to study intact and disordered human brain network formation and illustrate their utility in therapeutic discovery.

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Section: Rett Syndrome Fusion Organoids Exhibit Hypersynchronous Neurmentioning

confidence: 99%

Identification of neural oscillations and epileptiform changes in human brain organoids

Samarasinghe

Miranda

Buth

et al. 2019

Preprint

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“…S9). While PI3K/AKT (a hub in DE-ASD and XP-ASD networks) promotes proliferation and survival, many of the genes that are only hub in the XP-ASD network, including NRAS, ERK 1/2, and PTEN, can trigger differentiation of neural progenitor cells by mediating PI3K/AKT and its downstream pathways 3,44 .…”

Section: Signaling Pathways Are Central To the Leukocyte-based Networkmentioning

confidence: 99%

A perturbed gene network containing PI3K/AKT, RAS/ERK, WNT/β-catenin pathways in leukocytes is linked to ASD genetics and symptom severity

Gazestani

Pramparo

Nalabolu

et al. 2018

Preprint

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Hundreds of genes are implicated in autism spectrum disorder (ASD) but the mechanisms through which they contribute to ASD pathophysiology remain elusive. Here, we analyzed leukocyte transcriptomics from 1-4 year-old male toddlers with ASD or typical development from the general population. We discovered a perturbed gene network that includes genes that are highly expressed during fetal brain development and which is dysregulated in hiPSC-derived neuron models of ASD. Highconfidence ASD risk genes emerge as upstream regulators of the network, and many risk genes may impact the network by modulating RAS/ERK, PI3K/AKT, and WNT/β-catenin signaling pathways. We found that the degree of dysregulation in this network correlated with the severity of ASD symptoms in the toddlers.These results demonstrate how the heterogeneous genetics of ASD may dysregulate a core network to influence brain development at prenatal and very early postnatal ages and, thereby, the severity of later ASD symptoms. that the network is mostly preserved at the co-expression level between ASD leukocytes and prenatal brain.Specifically, the direction of correlations (i.e., positive or negative) in the leukocyte transcriptome of subjects with ASD is mostly preserved in prenatal and early postnatal brain ( Fig. 2d). Importantly, this preservation of co-expression was significantly higher in the DE-ASD network than in the DE-TD network (p-value <10 -16 ; Fig. S6). rASD genes are associated with the DE-ASD networkWe next analyzed the DE-ASD network in the context of other studies to test the relevance of our DE-ASD network to ASD. Parikshak et al. previously reported gene co-expression modules associated with cortical laminae development during prenatal and early postnatal ages 11 . A subset of these modules show enrichment in rASD genes 11 . We examined the overlap of our leukocyte-derived network with all modules from Parikshak et al 11 . The DE-ASD network preferentially overlapped with rASD gene-enriched modules from that study ( Fig. 2e). This suggests that our DE-ASD network is functionally related to rASD genes during neocortical development. Our DE-ASD network also overlapped with the networks of rASD genes reported in other studies 7,9 , indicating the robustness of the results (Fig. 2e). Intriguingly, the prenatal brain co-expression network of high-confidence rASD genes was more similar to that of ASD leukocytes than TD leukocytes ( Fig. 2f), suggesting that neurodevelopmental transcriptional programs related to rASD genes might be more active in the leukocyte transcriptome of toddlers with ASD than in that of TD toddlers.With the observed overlap patterns, we next tested for enrichment of rASD genes in the DE-ASD network. For this analysis, we considered different rASD gene lists of different size and varying confidence levels (Methods). Surprisingly, this analysis demonstrated that rASD genes are not enriched in the DE-ASD network (p-value >0.19). The DE-ASD network is enriched for regulatory targets of rASD genesMany high confidence rASD...

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“…Organoids. Organoids were grown according to the protocol by Lancaster et al 59 , with the addition of dual SMAD inhibition between d6 and d9 to increase neural differentiation as previously described 60 . Organoids were grown from iPSC cells (System Biosciences, #SC101A-1).…”

Section: Discussionmentioning

confidence: 99%

Ultrafast immunostaining of organ-scale tissues for scalable proteomic phenotyping

Yun

Park

Cho

et al. 2019

Preprint

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Studying the function and dysfunction of complex biological systems necessitates comprehensive understanding of individual cells. Advancements in three-dimensional (3D) tissue processing and imaging modalities have enabled rapid visualization and phenotyping of cells in their spatial context. However, system-wide interrogation of individual cells within large intact tissue remains challenging, low throughput, and error-prone owing to the lack of robust labeling technologies.Here we introduce a rapid, versatile, and scalable method, eFLASH, that enables complete and uniform labeling of organ-scale tissue within one day. eFLASH dynamically modulates chemical transport and reaction kinetics to establish system-wide uniform labeling conditions throughout the day-long labeling period. This unique approach enables the same protocol to be compatible with a wide range of tissue types and probes, enabling combinatorial molecular phenotyping across different organs and species. We applied eFLASH to generate quantitative maps of various cell types in mouse brains. We also demonstrated multidimensional cell profiling in a marmoset brain block. We envision that eFLASH will spur holistic phenotyping of emerging animal models and disease models to help assess their functions and dysfunctions.

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MeCP2-regulated miRNAs control early human neurogenesis through differential effects on ERK and AKT signaling

Cited by 220 publications

References 76 publications

Identification of neural oscillations and epileptiform changes in human brain organoids

Identification of neural oscillations and epileptiform changes in human brain organoids

A perturbed gene network containing PI3K/AKT, RAS/ERK, WNT/β-catenin pathways in leukocytes is linked to ASD genetics and symptom severity

Ultrafast immunostaining of organ-scale tissues for scalable proteomic phenotyping

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