Biology subjects

Chua, J. J. E.

Publications and source records attributed to Chua, J. J. E..

2 recordsLinked to original sources

bioRxiv2022

Phosphorylation Determines Whether Neuroligin-3 is at Excitatory or Inhibitory Synapses in Different Regions of the Brain

Neuroligin-3 is a postsynaptic adhesion molecule involved in development, function, and pathologies of synapses in the brain. It is a genetic cause of autism and a potent component of the tumor microenvironment in gliomas. There are four Neuroligins that operate at distinct synapse types, selectively interacting with presynaptic adhesion and postsynaptic scaffold proteins. We investigated the subcellular localization and scaffold specificities of synaptic Neuroligin-3 and demonstrate an unexpected pattern of localization to excitatory synapses in cortical areas, and inhibitory synapses in subcortical areas. Using phosphoproteomics, we identify Neuroligin-3-specific serine phosphorylation in cortex and hippocampus that obstructs a key binding site for inhibitory synapse scaffolds. Using in utero CRISPR/Cas9 knockout and replacement with phosphomimetic mutants, we demonstrate that phosphorylation at this site determines excitatory versus inhibitory synapse localization of Neuroligin-3 in vivo. Our data reveal a mechanism that differentially regulates the balance of Neuroligin-3 between excitatory and inhibitory synapses, adding to our emerging understanding of their role in the development of brain connectivity and associated pathologies.

neuroscience↗

bioRxiv2022

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

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.

neuroscience↗