Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Disease-related AUTS2 disruption causes an imbalance of neuronal/glial lineage specification through the WNT/β-catenin pathway

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE255185 | GEO | 2024/09/27

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Individuals with disruptions in the Autism Susceptibility Candidate 2 (AUTS2) gene frequently exhibit symptoms like intellectual disability, microcephaly, growth retardation, and distinct skeletal and facial differences. The role of AUTS2 in neurodevelopment has been explored using animal models and in vitro embryonic stem cell models. However, the precise molecular mechanisms through which AUTS2 influences neurodevelopment, particularly in humans, are not thoroughly understood. To address this, our study employs a 3D human organoid culture system, in combination with genetic, genomic, cellular, and molecular approaches, to investigate how AUTS2 impacts neurodevelopment through cellular signaling pathways. We used CRISPR/Cas9 technology to create AUTS2-deficient human embryonic stem cells (hESCs), replicating a 190kb genetic deletion observed in a patient. These cells were then differentiated into cerebral organoids. Our single-cell RNA sequencing (scRNA-seq) analysis of these organoids indicates that the absence of AUTS2 results in a significant reduction in neuron-related cells and an increase in choroid plexus (ChP) epithelial cells. Notably, our research reveals that AUTS2 negatively regulates the Wnt/β-catenin signaling pathway, evidenced by the observed overactivation of this pathway in AUTS2-deficient organoids as well as in a luciferase reporter cell line with AUTS2 deletion. Importantly, treating the AUTS2-deficient cerebral organoids with a Wnt inhibitor ameliorated the abnormalities in neuronal differentiation. This study offers new insights into the role of AUTS2 in neurodevelopment and suggests new potential targeted therapies for NDDs.

2024-09-27 | GSE255184 | GEO

2024-09-27 | GSE255183 | GEO

Project description:Disease-related AUTS2 disruption causes an imbalance of neuronal/glial lineage specification through the WNT/β-catenin pathway

| PRJNA1073901 | ENA

AUTS2 disruption causes neuronal differentiation defects in human cerebral organoids through hyperactivation of the WNT/β-catenin pathway

Project description: Not available

| S-EPMC11341827 | biostudies-literature

Project description:Disease-related AUTS2 disruption causes an imbalance of neuronal/glial lineage specification through the WNT/β-catenin pathway (RNA-Seq).

| PRJNA1073898 | ENA

Project description:Disease-related AUTS2 disruption causes an imbalance of neuronal/glial lineage specification through the WNT/β-catenin pathway (scRNA-Seq).

| PRJNA1073913 | ENA

Wnt signaling though beta-catenin is required for prostate lineage specification.

Project description:Androgens initiate a complex network of signals within the UGS that trigger prostate lineage commitment and bud formation. Given its contributions to organogenesis in other systems, we investigated a role for canonical Wnt signaling in prostate development. We developed a new method to achieve complete deletion of beta-catenin, the transcriptional coactivator required for canonical Wnt signaling, in early prostate development. Beta-catenin deletion abrogated canonical Wnt signaling and yielded prostate rudiments that exhibited dramatically decreased budding and failed to adopt prostatic identity. This requirement for canonical Wnt signaling was limited to a brief critical period during the initial molecular phase of prostate identity specification. Deletion of beta-catenin in the adult prostate did not significantly affect organ homeostasis. Collectively, these data establish that beta-catenin and Wnt signaling play key roles in prostate lineage specification and bud outgrowth.

| S-EPMC3472417 | biostudies-literature

Lineage specification of parietal epithelial cells requires β-catenin/Wnt signaling.

Project description:β-Catenin/Wnt signaling is essential during early inductive stages of kidney development, but its role during postinductive stages of nephron development and maturation is not well understood. In this study, we used Pax8Cre mice to target β-catenin deficiency to renal epithelial cells at the late S-shaped body stage and the developing collecting ducts. The conditional β-catenin knockout mice formed abnormal kidneys and had reduced renal function. The kidneys were hypoplastic with a thin cortex; a superficial layer of tubules was missing. A high proportion of glomeruli had small, underdeveloped capillary tufts. In these glomeruli, well differentiated podocytes replaced parietal epithelial cells in Bowman's capsule; capillaries toward the outer aspect of these podocytes mimicked the formation of glomerular capillaries. Tracing nephrogenesis in embryonic conditional β-catenin knockout mice revealed that these "parietal podocytes" derived from precursor cells in the parietal layer of the S-shaped body by direct lineage switch. Taken together, these findings demonstrate that β-catenin/Wnt signaling is important during the late stages of nephrogenesis and for the lineage specification of parietal epithelial cells.

| S-EPMC3269917 | biostudies-literature

Long noncoding RNAs in neuronal-glial fate specification and oligodendrocyte lineage maturation.

Project description:Long non-protein-coding RNAs (ncRNAs) are emerging as important regulators of cellular differentiation and are widely expressed in the brain.Here we show that many long ncRNAs exhibit dynamic expression patterns during neuronal and oligodendrocyte (OL) lineage specification, neuronal-glial fate transitions, and progressive stages of OL lineage elaboration including myelination. Consideration of the genomic context of these dynamically regulated ncRNAs showed they were part of complex transcriptional loci that encompass key neural developmental protein-coding genes, with which they exhibit concordant expression profiles as indicated by both microarray and in situ hybridization analyses. These included ncRNAs associated with differentiation-specific nuclear subdomains such as Gomafu and Neat1, and ncRNAs associated with developmental enhancers and genes encoding important transcription factors and homeotic proteins. We also observed changes in ncRNA expression profiles in response to treatment with trichostatin A, a histone deacetylase inhibitor that prevents the progression of OL progenitors into post-mitotic OLs by altering lineage-specific gene expression programs.This is the first report of long ncRNA expression in neuronal and glial cell differentiation and of the modulation of ncRNA expression by modification of chromatin architecture. These observations explicitly link ncRNA dynamics to neural stem cell fate decisions, specification and epigenetic reprogramming and may have important implications for understanding and treating neuropsychiatric diseases.

| S-EPMC2829031 | biostudies-literature

AUTS2 Controls Neuronal Lineage Choice Through a Novel PRC1-Independent Complex and BMP Inhibition.

Project description:Despite a prominent risk factor for Neurodevelopmental disorders (NDD), it remains unclear how Autism Susceptibility Candidate 2 (AUTS2) controls the neurodevelopmental program. Our studies investigated the role of AUTS2 in neuronal differentiation and discovered that AUTS2, together with WDR68 and SKI, forms a novel protein complex (AWS) specifically in neuronal progenitors and promotes neuronal differentiation through inhibiting BMP signaling. Genomic and biochemical analyses demonstrated that the AWS complex achieves this effect by recruiting the CUL4 E3 ubiquitin ligase complex to mediate poly-ubiquitination and subsequent proteasomal degradation of phosphorylated SMAD1/5/9. Furthermore, using primary cortical neurons, we observed aberrant BMP signaling and dysregulated expression of neuronal genes upon manipulating the AWS complex, indicating that the AWS-CUL4-BMP axis plays a role in regulating neuronal lineage specification in vivo. Thus, our findings uncover a sophisticated cellular signaling network mobilized by a prominent NDD risk factor, presenting multiple potential therapeutic targets for NDD.

| S-EPMC9905272 | biostudies-literature