Abstract
The molecular basis of how chromosome 16p13.11 microduplication leads to major psychiatric disorders is unknown. Here we have undertaken brain imaging of patients carrying microduplications in chromosome 16p13.11 and unaffected family controls, in parallel with iPS cell-derived cerebral organoid studies of the same patients. Patient MRI revealed reduced cortical volume, and corresponding iPSC studies showed neural precursor cell (NPC) proliferation abnormalities and reduced organoid size, with the NPCs therein displaying altered planes of cell division. Transcriptomic analyses of NPCs uncovered a deficit in the NFκB p65 pathway, confirmed by proteomics. Moreover, both pharmacological and genetic correction of this deficit rescued the proliferation abnormality. Thus, chromosome 16p13.11 microduplication disturbs the normal programme of NPC proliferation to reduce cortical thickness due to a correctable deficit in the NFκB signalling pathway. This is the first study demonstrating a biologically relevant, potentially ameliorable, signalling pathway underlying chromosome 16p13.11 microduplication syndrome in patient-derived neuronal precursor cells.
Highlights
Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Species-specific evolutionary expansion of cortical structure and circuitry underlies the unique range of human cognitive abilities
When Anterior Neuronal Precursor Cells (NPCs) (aNPCs) were differentiated by plate down in default media supplemented with forskolin, BDNF and GDNF (Supplementary Figure 3c-d), immunocytochemistry at 35 days revealed predominantly neuronal cultures with
Human induced-pluripotent stem cell (iPSC) models when applied to genetically stratified cohorts are powerful tools to dissect the molecular and cellular underpinnings of neurodevelopmental disorders [20, 41,42,43,44]
Summary
Species-specific evolutionary expansion of cortical structure and circuitry underlies the unique range of human cognitive abilities. Human induced-pluripotent stem cell (iPSC) technology, coupled to genetic discoveries, and the ability to reconstruct 3D cortical structures offers an unprecedented opportunity to better understand the mechanisms underlying major psychiatric disorders. Copy number variations (CNVs), such as those found at chromosome 16p13.11 locus are associated with a range of phenotypically different neurodevelopmental disorders including SCZ [1,2,3,4], intellectual disability [5, 6] and ASD [5], which suggest that the locus contains dosage-sensitive gene(s) with a critical role in neurodevelopment. In a Scottish population sample we found a fourfold excess of duplications at the 16p13.1 locus in SCZ patients compared to controls [7]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
