Description:

Joseph Gleeson, MD

The developmental origins and lineage relationships of human CNS cells remain poorly understood. Neural cells often arise far from their final destinations, following complex, evolutionary constrained migration routes. While vertebrate models provide critical insight, they tend to fall short modeling of neuropsychiatric and other conditions like neural tube defects. Differences between mouse and human are emerging that could help explain vulnerabilities, especially for certain cell populations implicated in disease risk. Traditional lineage-tracing methods are infeasible in humans. To overcome this, we leverage somatic mosaic variants as natural barcodes to map neurogenesis in the human brain. Neural somatic mosaicism refers to the presence of genetic mosaic variants within cells. Mosaic variants can occur from embryogenesis through adulthood, and are faithfully inherited by daughter cells. While some mosaic variants lead to disease, the vast majority are benign, where they can serve as inert lineage barcodes. We have developed methodology to interrogate mosaic variants in healthy humans to reveal patterns of neurogenesis that are surprisingly distinct in some ways from prior vertebrate model data. (1) Telencephalic cells are lineage-restricted at the midline before anterior–posterior restriction. (2) A subset of interneurons derives from dorsal neocortical progenitors. (3) Neural crest clones migrate rostrocaudally within the neural tube, later segregating into either sensory or sympathetic ganglia. These lineage patterns diverge from vertebrate models, with implications for human-specific vulnerabilities to neurodevelopmental and neuropsychiatric disorders.