Elucidating ADNP Syndrome Gene Dysregulation through a Novel Approach in iPSC-Derived GABAergic Neuron Development [scRNA-seq]
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PROVIDER: PRJNA1162887 | ENA |
REPOSITORIES: ENA
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Project description:GABAergic interneurons are essential for maintaining neural circuit function, and their dysfunction is linked to a range of neurodevelopmental and neurodegenerative disorders. Traditional approaches for differentiating human pluripotent stem cells (PSCs) into neuronal cells are often hindered by challenges such as incomplete neural differentiation, prolonged culture times, and variability across PSC lines. To overcome these limitations, we developed an innovative strategy by combining the overexpression of transcription factors Ascl1 and Dlx2 with dual-SMAD and WNT inhibition, effectively driving the differentiation of PSCs into diverse, region-specific GABAergic neuron subtypes. Through single-cell sequencing, we thoroughly characterized the heterogeneity of these induced neurons (iNs) and uncovered the regulatory mechanisms underlying their fate specification. Our findings demonstrate the successful generation of multiple disease-relevant GABAergic neuron types. Furthermore, we investigated the impact of the ADNP syndrome-associated p.Tyr719* variant on GABAergic neuron differentiation, revealing that this mutation significantly alters neuronal subtype composition and synaptic transmission. This study advances our understanding of the diversity of PSC-derived GABAergic neurons and underscores their potential as models for exploring neurological disorders.
2025-01-03 | GSE277604 | GEO
Project description:GABAergic interneurons are essential for maintaining neural circuit function, and their dysfunction is linked to a range of neurodevelopmental and neurodegenerative disorders. Traditional approaches for differentiating human pluripotent stem cells (PSCs) into neuronal cells are often hindered by challenges such as incomplete neural differentiation, prolonged culture times, and variability across PSC lines. To overcome these limitations, we developed an innovative strategy by combining the overexpression of transcription factors Ascl1 and Dlx2 with dual-SMAD and WNT inhibition, effectively driving the differentiation of PSCs into diverse, region-specific GABAergic neuron subtypes. Through single-cell sequencing, we thoroughly characterized the heterogeneity of these induced neurons (iNs) and uncovered the regulatory mechanisms underlying their fate specification. Our findings demonstrate the successful generation of multiple disease-relevant GABAergic neuron types. Furthermore, we investigated the impact of the ADNP syndrome-associated p.Tyr719* variant on GABAergic neuron differentiation, revealing that this mutation significantly alters neuronal subtype composition and synaptic transmission. This study advances our understanding of the diversity of PSC-derived GABAergic neurons and underscores their potential as models for exploring neurological disorders.
2025-01-03 | GSE277602 | GEO
Project description:Elucidating ADNP Syndrome Gene Dysregulation through a Novel Approach in iPSC-Derived GABAergic Neuron Development [ADNP_scRNA-seq]
| PRJNA1162897 | ENA
Project description:Gene expression profiles of GABAergic neuron progenitors (GAD67-GFP-positive cells)
2012-12-31 | E-MTAB-904 | biostudies-arrayexpress
Project description:The putative transcription factor, activity-dependent neuroprotective protein (ADNP) is a zinc finger and homeodomain - like profile containing protein. ADNP knockout mice die at day 9 of gestation. To reveal ADNP-associated pathways, a 22,690- Affymetrix probe array was used on ADNP knockout and control embryos. References:; Complete sequence of a novel protein containing a femtomolar-activity-dependent neuroprotective peptide. J Neurochem. 1999 Mar;72(3):1283-93. PMID: 10037502 [PubMed - indexed for MEDLINE]; Cloning and characterization of the human activity-dependent neuroprotective protein. J Biol Chem. 2001 Jan 5;276(1):708-14. PMID: 11013255 [PubMed - indexed for MEDLINE]; Activity-dependent neuroprotective protein: a novel gene essential for brain formation. Brain Res Dev Brain Res. 2003 Aug 12;144(1):83-90. PMID: 12888219 [PubMed - indexed for MEDLINE] Experiment Overall Design: To identify downstream target genes of ADNP, we examined global gene expression profiles of whole E9 knockout embryos (KO - ADNP -l-), their wild-type (WT - ADNP +l+ ) and their heterozygous (H - ADNP âl+ ) littermates, using the Affymetrix Murine Genome 430A oligonucleotide microarrays. Gestation day 9 was chosen as it is the period at which embryos lacking ADNP exhibit distinct morphological and developmental changes prior to degeneration and in uterus absorption. Total RNA was extracted from four ADNP knockout embryos, four normal embryos and six heterozygous embryos. A pool of two genotype identical littermates was used on seven different arrays (pooling of two embryos was necessary to obtain enough RNA on each of the gene microarrays).
2008-06-12 | E-GEOD-4068 | biostudies-arrayexpress
Project description:Intermediate progenitors of GABAergic neurons obtained from the mouse embryo neocortex at E18. Additional info: http://srv02.medic.kumamoto-u.ac.jp/dept/morneuro/en_r_micro.html
2010-12-01 | E-MTAB-452 | biostudies-arrayexpress
Project description:We report age-differential synaptic plasticity deficits associated with cognitive inflexibility and CaMKIIa hyperactivity in Adnp-mutant mice. These mice show impaired and inflexible contextual learning and memory along with social and anxiety-related deficits in adults, long after the juvenile-stage decrease of ADNP protein levels to ~10% of the newborn level. Adnp-mutant mice show abnormally enhanced long-term potentiation in adults but not in juveniles. This is accompanied by CaMKIIa hyperactivity involving increased baseline autophosphorylation and altered phosphorylation of CaMKIIa substrates, as revealed by unbiased proteomic analyses.
2023-07-11 | PXD037325 | Pride
Project description:Expression data of Glutarmatergic neuron and GABAergic neruon induced from iPSCs
| PRJNA480293 | ENA
Project description:We have identified ADNP as an R-loop regulator using a proximity-dependent labeling system. We find that ADNP is necessary to suppress R-loops at its binding sites, and that deletion of the ADNP homeodomain reduces ADNP binding to chromatin and results in R-loop accumulation.
2021-11-15 | GSE171401 | GEO
Project description:Bipolar disorder (BP) is a recurring psychiatric condition characterized by alternating episodes of low energy (depressions) followed by manias (high energy). Cortical network activity produced by GABAergic interneurons may be critical in maintaining the balance in excitatory/inhibitory activity in the brain during development. Initially, GABAergic signaling is excitatory; with maturation, these cells undergo a functional switch that converts GABAA channels from depolarizing (excitatory) to hyperpolarizing (inhibitory), which is controlled by the intracellular concentration of two chloride transporters. The earliest, NKCC1, promotes chloride entry into the cell and depolarization, while the second (KCC2) stimulates movement of chloride from the neuron, hyperpolarizing it. Perturbations in the timing or expression of NKCC1/KCC2 may affect essential morphogenetic events including cell proliferation, migration, synaptogenesis and plasticity, and thereby the structure and function of the cortex. We derived induced pluripotent stem cells (iPSC) from BP patients and undiagnosed control (C) individuals, then modified a differentiation protocol to form GABAergic interneurons, harvesting cells at sequential stages of differentiation. qRT-PCR and RNA sequencing indicated that after six weeks of differentiation, controls transiently expressed high levels of NKCC1.
2024-07-23 | GSE272060 | GEO