FEZ1 participates in human embryonic brain development by modulating neuronal progenitor subpopulation specification...

Mutations in the human fasciculation and elongation protein zeta 1 (FEZ1) gene are found in schizophrenia and Jacobsen syndrome patients. Here, using human cerebral organoids (hCOs), we show that FEZ1 expression is turned on early during brain development and is detectable in both neuroprogenitor subtypes and immature neurons. FEZ1 deletion disrupts expression of neuronal and synaptic development genes. Using single-cell RNA sequencing, we detected abnormal expansion of homeodomain-only protein homeobox (HOPX)^- outer radial glia (oRG), concurrent with a reduction of HOPX⁺ oRG, in FEZ1-null hCOs. HOPX^- oRGs show higher cell mobility as compared to HOPX⁺ oRGs. Ectopic localization of neuroprogenitors to the outer layer is seen in FEZ1-null hCOs. Anomalous encroachment of TBR2⁺ intermediate progenitors into CTIP2⁺ deep layer neurons further indicated abnormalities in cortical layer formation these hCOs. Collectively, our findings highlight the involvement of FEZ1 in early cortical brain development and how it contributes to neurodevelopmental disorders.