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bioRxiv · 10.1101/2022.07.11.499073

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

Qu, Y.·An, O.·Yang, H.·Toh, Y.-C.·Chua, J. J. E.
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Abstract

Abnormal neuronal networks arising from perturbations during early brain development contribute to neurodevelopmental disorders. Mutations and deletions of human Fasciculation and Elongation Protein Zeta 1 (FEZ1) are found in schizophrenia and Jacobsen syndrome patients. However, its roles in human brain development and manifestation of clinical pathological symptoms remain unknown. Here, using human cerebral organoids (hCOs), we observed that FEZ1 expression is turned on early during brain development and is detectable in both neuroprogenitor subtypes and immature neurons. Deletion of FEZ1 disrupts expression of genes involved in neuronal and synaptic development. Using single-cell RNA sequencing, we further uncovered an abnormal expansion of homeodomain-only protein homeobox (HOPX)- outer radial glia (oRG) in FEZ1-null hCOs, occurring at the expense of HOPX+ oRG. HOPX- oRGs show higher cell mobility as compared to HOPX+ oRGs, which is accompanied by the ectopic localization of the neuroprogenitors to the outer layer of FEZ1-null hCOs. Moreover, abnormal encroachment of TBR2+ intermediate progenitors into CTIP2+ deep layer neurons indicated that cortical layer formation is disrupted in FEZ1-null hCOs. Collectively, our findings highlight the involvement of FEZ1 in early cortical brain development and how it contributes to neurodevelopmental disorders.

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Qu, Y., An, O., Yang, H., Toh, Y.-C., Chua, J. J. E.. 2022-07-13. FEZ1 participates in human embryonic brain development by modulating neuronal progenitor subpopulation specification and migration. https://doi.org/10.1101/2022.07.11.499073

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