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Aberrant pace of cortical neuron development in brain organoids from patients with 22q11.2 deletion syndrome and schizophrenia. [scRNA-Seq]

ABSTRACT: Adults and children with the 22q11.2 deletion syndrome (22q11.2DS) demonstrate cognitive, social and emotional impairments and markedly increased risk for schizophrenia (SCZ). The alterations in early human brain development resulting from this deletion remain unclear. Here we use organoid models of the developing human cerebral cortex derived from patients with 22q11.2DS and SCZ as well as unaffected controls to identify cell-type-specific developmental abnormalities that result from this genomic lesion. Using RNA-sequencing and follow-up experimental validation we find that loss of genes within the 22q11.2 locus leads to delayed development of cortical neurons.

ORGANISM(S): Homo sapiens

PROVIDER: GSE244005 | GEO | 2024/12/01

REPOSITORIES: GEO

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Project description:Induced pluripotent stem cell (iPSC) technology presents a unique opportunity to model schizophrenia (SCZ) and other neuropsychiatric disorders in vitro by providing investigators with the means to grow patient-specific neurons. Three approaches are possible regarding disease modeling for a genetically heterogenous disorder, like SCZ. One is the draw subjects from the general patient population who have suspected but undefined disease-causing genetic variants. Another is to focus on a common phenotype, such as clinical presentation, response to medications or age of onset. The third is to use patients who have on a common genetic etiology. We have chosen the latter approach and are developing a library of iPSCs from patients with SCZ who harbor chromosome 22q11.2 microdeletions. In this preliminary study involving 4 patients and 4 controls, gene expression profiling was carried out on early differentiating neurons using RNA-seq. Several important observations were made. First, despite the dramatic molecular changes that occur during the reprogramming of a somatic cell into an iPSC, and its subsequent differentiation into neurons, processes that require months of cultivation with multiple changes in growth medium and treatment with a variety of growth factors, we show that 22q11.2 haploinsufficiency at the DNA level is recapitulated in vitro by substantial decreases in the expression of nearly every gene in the deleted region. Overall, transcriptome profiling revealed significant changes in the expression of 604 genes (423 increased in the SCZ samples, 181 decreased; >1.5-fold change, uncorrected p<0.05). Among the differentially expressed genes were a number of SCZ candidates and genes involved in retinoic acid (RA) signaling. In addition, there was some overlap with the differentially expressed genes found in another study using SCZ patients who do not have 22q11.2 del, one of which was CYP26A1, which codes for one of the major enzymes involved in RA metabolism. Although the sample size in this preliminary study is small, the findings support the idea that dysregulated RA-signaling could be a potential target for therapeutic intervention in SZ associated with 22q11.2 del, and perhaps other subgroups of patients. 4 controls and 4 patients

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Aberrant pace of cortical neuron development in brain organoids from patients with 22q11.2 deletion syndrome and schizophrenia. [scRNA-Seq]

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