innsikt - Neurodevelopment - # Neurogenesis and neurodevelopmental deficits in Williams Syndrome

Aberrant Neurogenesis and Neurodevelopmental Deficits in a Human Forebrain Organoid Model of Williams Syndrome

Q: How could the insights from this study on the GTF2IRD1-TTR-ERK axis be leveraged to develop potential therapeutic interventions for Williams Syndrome

The insights from this study on the GTF2IRD1-TTR-ERK axis provide a promising avenue for developing potential therapeutic interventions for Williams Syndrome. One approach could involve targeting the dysregulated pathway components to restore normal neurodevelopment. For example, since the deficiency of GTF2IRD1 leads to reduced TTR expression, which in turn affects neurogenesis, one potential therapeutic strategy could involve gene therapy to restore GTF2IRD1 levels or enhance TTR expression. This could potentially be achieved through viral vectors or CRISPR-based gene editing techniques. Additionally, the use of small molecules or compounds that target the ERK signaling pathway, such as ERK inhibitors or activators, could also be explored to modulate neurodevelopmental deficits in Williams Syndrome. By targeting the key components of the GTF2IRD1-TTR-ERK axis, it may be possible to develop targeted therapies that address the underlying molecular mechanisms contributing to the neurological phenotypes in Williams Syndrome.

Q: What other key signaling pathways or molecular mechanisms might be involved in the aberrant neurogenesis and neurodevelopmental deficits observed in Williams Syndrome beyond the ones identified in this study

Beyond the GTF2IRD1-TTR-ERK axis identified in this study, there are likely other key signaling pathways and molecular mechanisms involved in the aberrant neurogenesis and neurodevelopmental deficits observed in Williams Syndrome. One potential pathway to explore is the Wnt signaling pathway, which has been implicated in neuronal development and differentiation. Dysregulation of Wnt signaling has been linked to neurodevelopmental disorders, and investigating its role in Williams Syndrome could provide valuable insights. Additionally, pathways involved in synaptic plasticity, such as the mTOR pathway, and neuroinflammatory pathways, such as the NF-kB pathway, may also play a role in the neurological phenotypes of Williams Syndrome. Exploring the crosstalk between these pathways and how they interact with the GTF2IRD1-TTR-ERK axis could provide a more comprehensive understanding of the molecular mechanisms underlying Williams Syndrome.

Q: Given the complex genotype-phenotype relationships in Williams Syndrome, how could future research further elucidate the contributions of individual WS-associated genes to the diverse neurological phenotypes observed in this disorder

Future research could further elucidate the contributions of individual WS-associated genes to the diverse neurological phenotypes observed in Williams Syndrome through a combination of genetic, cellular, and animal models. One approach could involve generating knockout or knock-in animal models for each of the WS-associated genes to study their individual effects on neurodevelopment. By comparing the phenotypes of these animal models, researchers can determine the specific contributions of each gene to the neurological deficits observed in Williams Syndrome. Additionally, utilizing advanced genetic editing techniques, such as CRISPR-Cas9, to manipulate the expression of individual WS genes in cellular models, such as iPSC-derived neurons, could provide valuable insights into their roles in neuronal development. Integrating multi-omics approaches, such as transcriptomics, epigenomics, and proteomics, could also help unravel the complex genotype-phenotype relationships in Williams Syndrome by providing a comprehensive view of the molecular pathways and networks involved in the disorder.

Grunnleggende konsepter

The GTF2IRD1-transthyretin-ERK axis plays a critical role in the neurodevelopmental deficits observed in Williams Syndrome.

Sammendrag

The study utilized human forebrain organoids derived from induced pluripotent stem cells (iPSCs) of Williams Syndrome (WS) patients to investigate the underlying mechanisms of the neuronal deficits associated with this disorder. The key findings are:

Neural progenitor cells (NPCs) in WS forebrain organoids displayed abnormal proliferation and differentiation capabilities, as well as impaired synapse formation. Bulk RNA-seq analysis revealed altered expression of genes related to neuronal development and neurogenesis.
Single-cell RNA-seq (scRNA-seq) data analysis showed an aberrant generation of excitatory neurons in WS organoids, with a decreased proportion of deep layer and upper layer projection neurons.
Mechanistically, the expression of transthyretin (TTR) was significantly decreased in WS forebrain organoids. The transcription factor GTF2IRD1, encoded by one of the WS-associated genes, binds to the TTR promoter and regulates its expression.
Exogenous TTR could activate the ERK signaling pathway and rescue the neurogenic deficits of WS forebrain organoids. Gtf2ird1-deficient mice also displayed similar neurodevelopmental deficits as observed in the WS organoids.

Collectively, the study reveals a critical function of the GTF2IRD1-TTR-ERK axis in regulating neurodevelopment and provides novel insights into the mechanisms underlying the abnormal neurogenesis in Williams Syndrome.

Customize Summary

Rewrite with AI

Generate Citations

Translate Source

To Another Language

Generate MindMap

from source content

Visit Source

biorxiv.org

Statistikk

"The expression of 23 WS genes significantly decreased in WS forebrain organoids compared to controls."
"Bulk RNA-seq revealed 758 up-regulated and 1003 down-regulated genes in WS brain organoids compared to controls."
"The proportion of CTIP2+ and TBR1+ neurons significantly decreased in WS forebrain organoids compared to controls."
"The protein levels of GTF2IRD1, p-ERK and TTR were significantly decreased in the cortex of Gtf2ird1+/- and Gtf2ird1-/- mice compared to wild-type mice."

Sitater

"Our study reveals critical function of GTF2IRD1 in regulating neurodevelopment of WS forebrain organoids and mice through regulating TTR-ERK pathway."
"Exogenous TTR can activate ERK signaling and rescue neurogenic deficits of WS forebrain organoids."
"Gtf2ird1 deficient mice display similar neurodevelopmental deficits as observed in WS organoids."

Viktige innsikter hentet fra

A human forebrain organoid model reveals the essential function of GTF2IRD1-TTR-ERK axis for the neurodevelopmental deficits of Williams Syndrome

by Zhao,X., Sun... klokken www.biorxiv.org 04-25-2024

https://www.biorxiv.org/content/10.1101/2024.04.25.591131v1

Dypere Spørsmål

How could the insights from this study on the GTF2IRD1-TTR-ERK axis be leveraged to develop potential therapeutic interventions for Williams Syndrome

The insights from this study on the GTF2IRD1-TTR-ERK axis provide a promising avenue for developing potential therapeutic interventions for Williams Syndrome. One approach could involve targeting the dysregulated pathway components to restore normal neurodevelopment. For example, since the deficiency of GTF2IRD1 leads to reduced TTR expression, which in turn affects neurogenesis, one potential therapeutic strategy could involve gene therapy to restore GTF2IRD1 levels or enhance TTR expression. This could potentially be achieved through viral vectors or CRISPR-based gene editing techniques. Additionally, the use of small molecules or compounds that target the ERK signaling pathway, such as ERK inhibitors or activators, could also be explored to modulate neurodevelopmental deficits in Williams Syndrome. By targeting the key components of the GTF2IRD1-TTR-ERK axis, it may be possible to develop targeted therapies that address the underlying molecular mechanisms contributing to the neurological phenotypes in Williams Syndrome.

What other key signaling pathways or molecular mechanisms might be involved in the aberrant neurogenesis and neurodevelopmental deficits observed in Williams Syndrome beyond the ones identified in this study

Beyond the GTF2IRD1-TTR-ERK axis identified in this study, there are likely other key signaling pathways and molecular mechanisms involved in the aberrant neurogenesis and neurodevelopmental deficits observed in Williams Syndrome. One potential pathway to explore is the Wnt signaling pathway, which has been implicated in neuronal development and differentiation. Dysregulation of Wnt signaling has been linked to neurodevelopmental disorders, and investigating its role in Williams Syndrome could provide valuable insights. Additionally, pathways involved in synaptic plasticity, such as the mTOR pathway, and neuroinflammatory pathways, such as the NF-kB pathway, may also play a role in the neurological phenotypes of Williams Syndrome. Exploring the crosstalk between these pathways and how they interact with the GTF2IRD1-TTR-ERK axis could provide a more comprehensive understanding of the molecular mechanisms underlying Williams Syndrome.

Given the complex genotype-phenotype relationships in Williams Syndrome, how could future research further elucidate the contributions of individual WS-associated genes to the diverse neurological phenotypes observed in this disorder

Future research could further elucidate the contributions of individual WS-associated genes to the diverse neurological phenotypes observed in Williams Syndrome through a combination of genetic, cellular, and animal models. One approach could involve generating knockout or knock-in animal models for each of the WS-associated genes to study their individual effects on neurodevelopment. By comparing the phenotypes of these animal models, researchers can determine the specific contributions of each gene to the neurological deficits observed in Williams Syndrome. Additionally, utilizing advanced genetic editing techniques, such as CRISPR-Cas9, to manipulate the expression of individual WS genes in cellular models, such as iPSC-derived neurons, could provide valuable insights into their roles in neuronal development. Integrating multi-omics approaches, such as transcriptomics, epigenomics, and proteomics, could also help unravel the complex genotype-phenotype relationships in Williams Syndrome by providing a comprehensive view of the molecular pathways and networks involved in the disorder.