A hPSCs-based model to study the biology of the schizophrenia and autism risk gene CYFIP1

• Main Author: Tamburini, Claudia
• Published: Cardiff University 2018
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.738424

Microdeletions and microduplications at the chromosomic locus ch15q11.2 have been linked to an increased risk of developing several psychiatric and neurodevelopmental conditions. Abnormal expression levels of CYFIP1, one of the genes within this region, have been shown by several studies to cause alterations to the morphology and physiology of neuronal cells. However, despite its specific expression in progenitors of the developing cortex, little is known about the role played by CYFIP1 in neural development. This thesis presents an investigation of the biological mechanisms, through which CYFIP1 affects cortex development in vitro using human embryonic stem cells (hESCs). To this end, lines of hESCs either expressing a CYFIP1 transgene (CYFIP1tg) or harbouring a loss-of-function deletion (CYFIP1ko) were derived to mimic increased and decreased level of CYFIP1 expression, respectively, and differentiated into cortical glutamatergic neurons. Disruptions to the normal levels of CYFIP1 resulted into abnormal formation of neural rosettes and altered kinetics of neuronal differentiation. Importantly, CYFIP1 overexpression seemed to promote self-renewal of the progenitor pool, while loss of this gene had an opposite effect. Whole-genome transcriptomic analysis revealed the dysregulation of numerous pathways, including WNT signalling, cell adhesion and mitochondria metabolism. In line with this, the expression levels of N-Cadherin and the phosphorylation pattern of β-Catenin suggested that the signalling axis involving these two proteins is altered in CYFIP1tg and CYFIP1ko cortical progenitors. Moreover, pharmacological inhibition of WNT and AKT, which mediate this signalling, was able to rescue the excessive proliferation of NPCs associated with CYFIP1 overexpression. Finally, the presence of altered mitochondrial dynamics in CYFIP1tg and CYFIP1ko NPCs and neurons was validated using a high-content screening system. These data demonstrate that CYFIP1 plays a role in the regulation of cortex development and, consequently, in the clinical manifestations associated with 15q11.2 CNVs. Furthermore, they strengthen the hypothesis of a developmental origin for psychiatric conditions like schizophrenia and autism spectrum disorders.