Single-cell transcriptomic analysis in Noonan syndrome-derived brain organoids

Abstract

Noonan syndrome (NS) is an autosomal dominant genetic disorder, dominantly caused by mutations in tyrosine phosphatase SHP2. Although NS patients frequently have a variety of neurological symptoms reported, it is still unclear how SHP2 mutations cause the neurodevelopmental abnormalities linked to this syndrome. Here, I report that NS-induced pluripotent stem cells (iPSCs) show abnormal development of excitatory neurons (ENs) in the differentiation process into cortical organoids (NS-COs). Although these organoids exhibit normal appearance, single-cell RNA sequencing uncovered that the EN population have been increased and several cortical layer markers are overexpressed in a patient-specific manner. Furthermore, upper layer marker SATB2 and the deep layer maker CTIP2 was co-expressed in the subpopulation of NS-ENs. In accordance with these findings, synaptic connections were also reduced in NS-COs. Collectively, our findings suggest that perturbed cortical layer identity and impeded neuronal connectivity contribute to the neurological manifestations of NS.