@article{cf1370aeb5be408ca0064203e937bf53,
title = "Impaired oxysterol-liver X receptor signaling underlies aberrant cortical neurogenesis in a stem cell model of neurodevelopmental disorder",
abstract = "The mechanisms by which genomic risks contribute to the onset of neuropsychiatric conditions remain a key challenge and a prerequisite for successful development of effective therapies. 15q11.2 copy number variation (CNV) containing the CYFIP1 gene is associated with autism and schizophrenia. Using stem cell models, we show that 15q11.2 deletion (15q11.2del) and CYFIP1 loss of function (CYFIP1-LoF) lead to premature neuronal differentiation, while CYFIP1 gain of function (CYFIP1-GoF) favors neural progenitor maintenance. CYFIP1 dosage changes led to dysregulated cholesterol metabolism and altered levels of 24S,25-epoxycholesterol, which can mimic the 15q11.2del and CYFIP1-LoF phenotypes by promoting cortical neuronal differentiation and can restore the impaired neuronal differentiation of CYFIP1-GoF neural progenitors. Moreover, the neurogenic activity of 24S,25-epoxycholesterol is lost following genetic deletion of liver X receptor (LXR{\ss}), while compound deletion of LXR{\ss} in CYFIP1-/- background rescued their premature neurogenesis. This work delineates LXR-mediated oxysterol regulation of neurogenesis as a pathological mechanism in neural cells carrying 15q11.2 CNV and provides a potential target for therapeutic strategies for associated disorders.",
keywords = "15q11.2 CNV, CP: Developmental biology, CP: Neuroscience, CYFIP1, human pluripotent stem cells (hPSCs), liver X receptor, neurogenesis, neuropsychiatric disorders, oxysterol",
author = "{De La Fuente}, {Daniel Cabezas} and Claudia Tamburini and Emily Stonelake and Robert Andrews and Jeremy Hall and Owen, {Michael J.} and Linden, {David E.J.} and Andrew Pocklington and Meng Li",
note = "Funding Information: We thank Drs. William Griffiths and Yuqin Wang for the mass spectrometry performed in their laboratories and for providing expert advice on oxysterol-related neuronal assays. We thank Drs. Stefanie Linden, Faraz Ali, Kali Barawi, Jacqueline Smith, and Alister Baird and support from Welsh National Center for Mental Health for providing 15q11.2del biopsies, and we also thank Dr. Craig Joyce for iPSC reprograming. RNA sequencing analysis was performed using the computational facilities of the Advanced Research Computing@Cardiff (ARCCA) Division, Cardiff University. This work was supported by a Wellcome Trust Strategic Award (100202/Z/12/Z) to M.J.O. J.H. D.E.J.L. M.L. and other co-PIs and funding from the Medical Research Council (MRC, grant no. MR/R022429/1 to M.L.). The mass spectrometry work and equipment was funded by Swansea University, the Biotechnology and Biological Sciences Research Council (BBSRC, grant no. BB/S019588/1), and the Wellcome Trust Strategic Award (100202/Z/12/Z) through M.L. E.S. is funded by a BBSRC SWBio PhD studentship. For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) license to any author-accepted manuscript version arising from this submission. M.L. C.T. and D.C.D.L.F. conceived the study and designed the experiments. D.C.D.L.F. and C.T. carried out and analyzed the hESC and hiPSC experiments. D.C.D.L.F. performed RNA-seq data analysis with support from A.P. and R.A. E.S. performed the sterol profiling and analyzed the data. D.E.J.L. J.H. and M.J.O. provided 15q11.2del carrier samples and contributed to general discussions throughout the work. M.L. C.T. and D.C.D.L.F. wrote the paper. All authors edited and approved the paper. The authors declare no competing financial interests. Funding Information: We thank Drs. William Griffiths and Yuqin Wang for the mass spectrometry performed in their laboratories and for providing expert advice on oxysterol-related neuronal assays. We thank Drs. Stefanie Linden, Faraz Ali, Kali Barawi, Jacqueline Smith, and Alister Baird and support from National Center for Mental Health for providing 15q11.2del biopsies, and we also thank Dr. Craig Joyce for iPSC reprograming. RNA sequencing analysis was performed using the computational facilities of the Advanced Research Computing@Cardiff (ARCCA) Division, Cardiff University. This work was supported by a Wellcome Trust Strategic Award ( 100202/Z/12/Z ) to M.J.O., J.H., D.E.J.L., M.L., and other co-PIs and funding from the Medical Research Council (MRC, grant no. MR/R022429/1 to M.L.). The mass spectrometry work and equipment was funded by Swansea University, the Biotechnology and Biological Sciences Research Council (BBSRC, grant no. BB/S019588/1 ), and the Wellcome Trust Strategic Award ( 100202/Z/12/Z ) through M.L. E.S. is funded by a BBSRC SWBio PhD studentship. For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) license to any author-accepted manuscript version arising from this submission. Publisher Copyright: {\textcopyright} 2024 The Author(s)",
year = "2024",
month = mar,
day = "26",
doi = "10.1016/j.celrep.2024.113946",
language = "English",
volume = "43",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "3",
}