Reversal of proliferation deficits caused by chromosome 16p13.11 microduplication through targeting NFκB signaling: an integrated study of patient-derived neuronal precursor cells, cerebral organoids and in vivo brain imaging
Research output: Contribution to journal › Journal article › Research › peer-review
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.
| Original language | English |
|---|---|
| Journal | Molecular Psychiatry |
| Volume | 24 |
| Issue number | 2 |
| Pages (from-to) | 294-311 |
| Number of pages | 18 |
| ISSN | 1359-4184 |
| DOIs | |
| Publication status | Published - 1 Feb 2019 |
| Externally published | Yes |
Bibliographical note
Funding Information:
Acknowledgements We would like to thank the individuals and their families who generously agreed to participate in this study. We are grateful to Ms. Alix Macdonald for human imaging support, Mr. Eddy Maher, Ms. Carol Delaney, Mrs. Mary Glancy for cytogenetics support, Mrs. Helen Caldwell for immunohistochemistry support, Drs. Ann Wheeler, Ahmed Fetit, Matthew Pearson and Laura Murphy for advanced imaging microscopy support, and to Mrs. Nicola Clements, Mrs. Karen Gladstone and Mrs. Rinku Rajan for generous help with tissue culture. We would also like to thank Professor Neil Perkins (Newcastle University) for gifting the pIRESpuro-RelA lentivirus, packaging and envelope plasmids. This research was funded by a Clinical Research Career Development Fellowship from The Wellcome Trust to MJ (103406/Z/13/Z) and The RS Macdonald Charitable Trust, and The Sackler Foundation. MB is supported by a University of Edinburgh Principal’s Career Development Scholarship. HCW is supported by a Dorothy Hodgkin Fellowship from the Royal Society, and NAV is supported by a Department of Biotechnology, Government of India fellowship. MRL is supported by Royal Society of Edinburgh/Caledonian Research Fund Personal Research Fellowship. EC was supported by a summer studentship from The Dr Hawden Trust to work with MJ. RF is a Wellcome Trust funded Translational Neuroscience PhD student. The Chandran Group is supported by DPUK funding, a MRC Stem Cell Partnership Grant (RA3624) and a MS Society Centre Award (RA43729). Generation of DISC1 iPSC-control lines was supported by a MRC grant (MR/J004367/1).
Publisher Copyright:
© 2018, The Author(s).
ID: 282253135