ArticleMolecular autism2023
Impaired neurogenesis and neural progenitor fate choice in a human stem cell model of SETBP1 disorder.
Article in Molecular autism, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 32 citations in OpenAlex.
- Article
- Molecular and clinical spectrum of epilepsy-dyskinesia syndromes: a cross-sectional study of 609 patients.Brain : a journal of neurology · 2026Article
- Cell-type-specific alternative splicing in the brain and kidney of a Setbp1S858R Schinzel-Giedion syndrome mouse.Disease models & mechanisms · 2026Article
- Cholesterol metabolism on stem cell fate determination: a frontier horizon.Stem cell research & therapy · 2025Review
- SETBP1 variants outside the degron disrupt DNA-binding, transcription and neuronal differentiation capacity to cause a heterogeneous neurodevelopmental disorder.Nature communications · 2025Article
- Autism risk genes converge onbioRxiv : the preprint server for biology · 2025Article
- Unlocking Hope: Therapeutic Advances and Approaches in Modulating the Wnt Pathway for Neurodegenerative Diseases.Molecular neurobiology · 2025Review
- Prenatal diagnosis of intellectual disability, autosomal dominant 29 with a nonsense pathogenic variant inFrontiers in genetics · 2025Article
- Case Report: Whole-exome sequencing revealed a de novo variant inFrontiers in genetics · 2025Article
- Rapid effects of valproic acid on the fetal brain transcriptome: implications for brain development and autism.Translational psychiatry · 2024Article
- Expression and regulation of SETBP1 in the song system of male zebra finches (Taeniopygia guttata) during singing.Scientific reports · 2024Article
- Identifying SETBP1 haploinsufficiency molecular pathways to improve patient diagnosis using induced pluripotent stem cells and neural disease modelling.Molecular autism · 2024Article
- Molecular mechanisms reconstruction from single-cell multi-omics data with HuMMuS.Bioinformatics (Oxford, England) · 2024Article
- Genetic Alterations in a Large Population of Italian Patients Affected by Neurodevelopmental Disorders.Genes · 2024Article
- The landscape of SETBP1 gene expression and transcription factor activity across human tissues.PloS one · 2024Article
- Epigenetic regulation of craniofacial development and disease.Birth defects research · 2024Review
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3 authors at 1 institution in 1 country.
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Abstract
backgroundDisruptions of SETBP1 (SET binding protein 1) on 18q12.3 by heterozygous gene deletion or loss-of-function variants cause SETBP1 disorder. Clinical features are frequently associated with moderate to severe intellectual disability, autistic traits and speech and motor delays. Despite the association of SETBP1 with neurodevelopmental disorders, little is known about its role in brain development.
methodsUsing CRISPR/Cas9 genome editing technology, we generated a SETBP1 deletion model in human embryonic stem cells (hESCs) and examined the effects of SETBP1-deficiency in neural progenitors (NPCs) and neurons derived from these stem cells using a battery of cellular assays, genome-wide transcriptomic profiling and drug-based phenotypic rescue.
resultsNeural induction occurred efficiently in all SETBP1 deletion models as indicated by uniform transition into neural rosettes. However, SETBP1-deficient NPCs exhibited an extended proliferative window and a decrease in neurogenesis coupled with a deficiency in their ability to acquire ventral forebrain fate. Genome-wide transcriptome profiling and protein biochemical analysis revealed enhanced activation of Wnt/β-catenin signaling in SETBP1 deleted cells. Crucially, treatment of the SETBP1-deficient NPCs with a small molecule Wnt inhibitor XAV939 restored hyper canonical β-catenin activity and restored both cortical and MGE neuronal differentiation. LIMITATIONS: The current study is based on analysis of isogenic hESC lines with genome-edited SETBP1 deletion and further studies would benefit from the use of patient-derived iPSC lines that may harbor additional genetic risk that aggravate brain pathology of SETBP1 disorder.
conclusionsWe identified an important role for SETBP1 in controlling forebrain progenitor expansion and neurogenic differentiation. Our study establishes a novel regulatory link between SETBP1 and Wnt/β-catenin signaling during human cortical neurogenesis and provides mechanistic insights into structural abnormalities and potential therapeutic avenues for SETBP1 disorder.
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