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

• Published in: iScience 2023-12, Vol.26 (12), p.108497-108497, Article 108497
• Main Authors: Qu, Yinghua, Lim, Jonathan Jun-Yong, An, Omer, Yang, Henry, Toh, Yi-Chin, Chua, John Jia En
• Format: Article
• Language: English
• Subjects: developmental neuroscience; molecular neuroscience; neuroscience
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2023.108497

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. [Display omitted] •FEZ1 expression is turned on early during human brain development•Deletion of FEZ1 causes expansion of HOPX− outer radial glial cells•Ectopic localization of neuroprogenitors occurs in the absence of FEZ1•Cortical layer formation is disrupted in the absence of FEZ1 Neuroscience; Molecular neuroscience; Developmental neuroscience