Gene expression profile comparision between developing internerurons of wild type and poly Alanine expanded ARX mutants
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PROVIDER: PRJNA1142601 | ENA |
REPOSITORIES: ENA
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Project description:To examine expression profile of the polyalanine expansion mutant in Arx during interneuron development, wild type (control) and the mutant's interneuron in Dlx5/6-GFP backaground was harvested with cell sorter at E14.5 stage. The total RNA was extracted and cDNA was synthesized. Gene expression profile was assayed on mouse affymatrix array.
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Project description:Infantile spasms (IS), a severe childhood epilepsy with an incidence of 1.6–4.5 per 10,000 live births, often lead to lifelong intellectual disability. Up to 5% of affected males carry mutations in the Aristaless-related homeobox (ARX) gene. The lack of human-specific models for developmental epilepsy limits progress, making organoids a promising alternative. We use human cortical (CO) and ganglionic eminence organoids (GEO) to model poly-alanine expansion (PAE) mutations in ARX. PAE mutations increase cortical progenitor proliferation and accelerate early cortical development. ARX expression is upregulated in patient-derived COs at 30 DIV, correlating with altered cell cycle gene expression. We observe enhanced, cell-autonomous interneuron migration, which is rescued by CXCR4 inhibition. ARXPAE assembloids exhibit early network hyperactivity. These findings highlight the utility of human brain organoids in uncovering ARXPAE-driven mechanisms and represent a critical step toward developing targeted therapies for IS and related developmental epilepsies.
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Project description:Abnormal cortical interneuron (cIN) development and function has been linked to neurodevelopmental disorders including developmental epilepsies, intellectual disabilities, and autism spectrum disorder. Mutations in ARX (aristaless-related homeobox) are associated with these disorders. Its differential expression in projection neuron- versus interneuron progenitors suggests ARX is one of the few genes with distinct functions in each progenitor type. To investigate how ARX regulates development of cINs, which originate from the ganglionic eminence (GE) and migrate to the cortex, we interrogated multiple GE-targeted Arx mutant mice. Our data demonstrates that ARX normally represses Nkx2.1 expression and promotes cell cycle exit of the progenitor cells. Furthermore, it plays key roles in cIN subtype specification and migration along the marginal zone, by directly binding to the regulatory sequences of genes modulating cell subtype specification and cell-cell communication. Together these findings provide new insights into the mechanisms underlying cIN development and migration and how they are disrupted in several related disorders.
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