SOX2 is essential for astrocyte maturation and its deletion leads to hyperactive behavior in mice.

Abstract

Children with SOX2 deficiency develop ocular disorders and extra-ocular CNS anomalies. Animal data show that SOX2 is essential for retinal and neural stem cell development. In the CNS parenchyma, SOX2 is primarily expressed in astroglial and oligodendroglial cells. Here, we report a crucial role of astroglial SOX2 in postnatal brain development. Astroglial Sox2-deficient mice develop hyperactivity in locomotion and increased neuronal excitability in the corticostriatal circuit. Sox2 deficiency inhibits postnatal astrocyte maturation molecularly, morphologically, and electrophysiologically without affecting astroglia proliferation. Mechanistically, SOX2 directly binds to a cohort of astrocytic signature and functional genes, the expression of whichissignificantly reduced in Sox2-deficient CNS and astrocytes. Consistently, Sox2 deficiency remarkably reduces glutamate transporter expression and compromised astrocyte function of glutamate uptake.Our study provides insights into the cellular mechanisms underlying brain defects in children with SOX2 mutations and suggests a link of astrocyte SOX2 with extra-ocular abnormalities in SOX2-mutant subjects.