Roles of Arx in developing interneuron [scRNA-seq]

Abnormal cortical interneuron (cIN) development and function has been linked to neurodevelopmental disorders including developmental epilepsies, intellectual disabilities, and autism spectrum disorders. Mutations in ARX (aristaless-related homeobox), an X-linked transcription factor, are associated with these disorders. Its differential expression in pallial projection neuron- versus subpallial interneuron progenitors, suggests ARX is one of a few genes with distinct functions in each progenitor type. To investigate how ARX regulates development of cINs which originate from the subpallial 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 and promotes cIN differentiation. Furthermore, it plays a key role 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.