Emily Stonelake co-authors publication in ‘Cell Reports’

Emily Stonelake is a third-year SWBio student at Swansea and Cardiff. She is a co-author on a publication investigating the role of oxysterol-Liver X receptor signalling in altered cortical neurogenesis in a stem cell model of a neurodevelopmental disorder, published in Cell Reports. Here, Emily tells us about her findings

Neurodevelopmental disorders, such as autism and schizophrenia, are believed to originate during early brain development with shared genetic etiology. Copy number variations (CNVs) at chromosomal locus 15q11.2 (BP1-BP2) involve either deletions or duplications of this region of the genome and have been linked to an increased risk of developing these disorders. The CYFIP1 gene located in this region is thought to be the strongest candidate underlying the link between 15q11.2 CNV and neuropsychiatric symptoms.

Using stem cell models, this article demonstrates that deletion of the 15q11.2 region (15q11.2del) and loss of function of CYFIP1 (CYFIP1-LoF) result in premature neuronal differentiation. Conversely, gain of function of CYFIP1 (CYFIP1-GoF), as a model of the duplication of 15q11.2, reveals a bias toward maintenance of neural progenitors. Interestingly, this study further reveals dysregulated cholesterol metabolism and altered levels of the oxysterol 24S,25-epoxycholesterol in cells with altered levels of CYFIP1.
Altered cholesterol metabolism has been implicated in the pathogenesis of several neurodevelopmental disorders. Oxysterols are oxidised forms of cholesterol or its precursors and many have been shown to have biological activity, including acting as ligands to liver X receptors (LXRs).

Remarkably, 24S,25-epoxycholesterol was found to mimic the phenotypes associated with 15q11.2del and CYFIP1-LoF by promoting cortical neuronal differentiation. Importantly, it was also capable of rescuing the impaired neuronal differentiation in CYFIP1-GoF neural progenitors. We further identified liver X receptor beta (LXRβ) as a key player mediating the neurogenic effects of 24S,25-epoxycholesterol. Genetic deletion of LXRβ abolished the neurogenic activity of 24S,25-epoxycholesterol, whilst compound deletion of LXRβ in CYFIP1-deficient cells rescued premature neurogenesis. This work outlines LXR-mediated oxysterol regulation of neurogenesis as a pathological mechanism in neural cells carrying the 15q11.2 CNV and provides a potential target for therapeutic strategies for associated disorders.

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