Impaired oxysterol-liver X receptor signaling underlies aberrant cortical neurogenesis in a human stem cell model of neurodevelopmental disorder

Cabezas De La Fuente, Daniel, Tamburini, Claudia, Stonelake, Emily, Andrews, Robert, Hall, Jeremy ORCID: https://orcid.org/0000-0003-2737-9009, Owen, Michael ORCID: https://orcid.org/0000-0003-4798-0862, Linden, David ORCID: https://orcid.org/0000-0002-5638-9292, Pocklington, Andrew ORCID: https://orcid.org/0000-0002-2137-0452 and Li, Meng ORCID: https://orcid.org/0000-0002-4803-4643 2024. Impaired oxysterol-liver X receptor signaling underlies aberrant cortical neurogenesis in a human stem cell model of neurodevelopmental disorder. Cell Reports 43 (3) , 113946. 10.1016/j.celrep.2024.113946

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Abstract

The mechanisms by which genomic risks contribute to the onset of neuropsychiatric conditions remains a key challenge and a prerequisite for successful development of effective therapies. 15q11.2 CNV containing the CYFIP1 gene is associated with autism and schizophrenia. Using stem cell models we show that 15q11.2 deletion and CYFIP1-LoF leads to premature neuronal differentiation while 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 phenotype by promoting cortical neuronal differentiation and restore the impaired neuronal differentiation of CYFIP1-GoF neural progenitors. Moreover, the neurogenic activity of 24S,25-epoxycholesterol is lost following genetic deletion of LXR while compound deletion of LXR in CYFIP1-/- background rescued their premature neurogenesis. This work delineates LXR mediated oxysterol regulation of neurogenesis as a pathological mechanism in neural cells carrying 15q11.2CNV and provides a potential target for therapeutic strategies for associated disorders.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Advanced Research Computing @ Cardiff (ARCCA) Biosciences MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) Medicine Neuroscience and Mental Health Research Institute (NMHRI)
Publisher:	Cell Press
ISSN:	2211-1247
Date of First Compliant Deposit:	28 February 2024
Date of Acceptance:	26 February 2024
Last Modified:	11 Jun 2024 15:26
URI:	https://orca.cardiff.ac.uk/id/eprint/166610

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