Cxcr4 and Ackr3 regulate allocation of caudal ganglionic eminence-derived interneurons to superficial cortical layers

The function of the cerebral cortex depends on various types of interneurons (cortical interneurons [cINs]) and their appropriate allocation to the cortical layers. Caudal ganglionic eminence-derived cINs (cGE-cINs) are enriched in superficial layers. Developmental mechanisms directing cGE-cINs toward superficial layers remain poorly understood. We examine how developmental and final positioning of cGE-cINs are influenced by the Cxcl12, Cxcr4, Ackr3 module, the chief attractant system guiding medial ganglionic eminence-derived cINs (mGE-cINs). We find that Cxcl12 attracts cGE-cINs through Cxcr4 and supports their layer-specific positioning in the developing cortex. This requires the prevention of excessive Cxcr4 stimulation by Ackr3-mediated Cxcl12 sequestration. Postnatally, Ackr3 confines Cxcl12 action to the marginal zone. Unlike mGE-cINs, cGE-cINs continue to express Cxcr4 at early postnatal stages, which permits cGE-cINs to become positioned in the forming layer 1. Thus, chemoattraction by Cxcl12 guides cGE-cINs and holds them in superficial cortical layers.