CXCL12 regulates migration and final layer allocation of caudal ganglionic eminence-derived GABAergic neurons in the cerebral cortex

• Applicant: Professor Dr. Ralf Stumm
• Subject Area: Developmental Neurobiology
• Term: from 2017 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 391088085

GABAergic neurons of the cerebral cortex (interneurons) are a highly specialized heterogeneous cell population that exerts essential inhibitory control over cortical network activity. Defects in the development of these neurons lead to neurological and probably neuropsychiatric disorders. We investigate how the migration of these neurons is regulated during ontogenesis. Approximately 70% of interneurons originate in the medial ganglionic eminence (mGE) and 30% in the caudal ganglionic eminence (cGE). cGE-derived interneurons are distinct from their mGE-derived counterparts with regard to their progenitors, genetic programs and functions. They are also generated later, undergo unique surface-directed migration during postnatal corticogenesis and integrate mostly into superficial layers (mGE-derived interneurons are homogeneously distributed across layers II-VI). Little is known which guidance molecules organize migration and layering of cGE-derived interneurons. We and others established that CXCL12 signaling through the chemokine receptor CXCR4 is essential for early migration of mGE-derived interneurons. Although CXCL12 has only small effects on final layering of these cells, defective regulation of the CXCL12/CXCR4 pathway in interneuron precursors has been implicated in the pathobiology of schizophrenia. We now demonstrate that migration and final layering of cGE-derived interneurons are severely perturbed in mice with defects in the CXCL12 signaling module. We also found that CXCR4 expression is maintained in many cGE-derived interneurons during late corticogenesis while being switched off in most mGE-derived cells. We established in utero electroporation, live cell microscopy and unique genetic tools enabling us to test the hypothesis that such differences in the temporal CXCR4 expression profile contribute to different migration behavior and layering of interneuron subtypes in the cerebral cortex.

• DFG Programme: Research Grants