Hominini-specific regulation of CBLN2 increases prefrontal spinogenesis

The similarities and differences between nervous systems of various species result from developmental constraints and specific adaptations1–4. Comparative analyses of the prefrontal cortex (PFC), a cerebral cortex region involved in higher-order cognition and complex social behaviours, have identified true and potential human-specific structural and molecular specializations4–8, such as an exaggerated PFC-enriched anterior–posterior dendritic spine density gradient5. These changes are probably mediated by divergence in spatiotemporal gene regulation9–17, which is particularly prominent in the midfetal human cortex15,18–20. Here we analysed human and macaque transcriptomic data15,20 and identified a transient PFC-enriched and laminar-specific upregulation of cerebellin 2 (CBLN2), a neurexin (NRXN) and glutamate receptor-δ GRID/GluD-associated synaptic organizer21–27, during midfetal development that coincided with the initiation of synaptogenesis. Moreover, we found that species differences in level of expression and laminar distribution of CBLN2 are, at least in part, due to Hominini-specific deletions containing SOX5-binding sites within a retinoic acid-responsive CBLN2 enhancer. In situ genetic humanization of the mouse Cbln2 enhancer drives increased and ectopic laminar Cbln2 expression and promotes PFC dendritic spine formation. These findings suggest a genetic and molecular basis for the anterior-posterior cortical gradient and disproportionate increase in the Hominini PFC of dendritic spines and a developmental mechanism that may link dysfunction of the NRXN–GRID–CBLN2 complex to the pathogenesis of neuropsychiatric disorders.