Cellular and Molecular Features of Human Brain Expansion and Evolution

The developing human brain contains a huge number of cells whose identities have not yet been fully explored but whose specific molecular and functional features lead to the development of human specific abilities. We are using single cell approaches to establish an integrative definition of cell types in the developing human neocortex. Our single cell genomics analysis has revealed the molecular identity of a key human progenitor cell type, termed an outer radial glia cell (oRG). The developing human cortex contains a massively expanded progenitor region that is enriched in oRG cells that are thought to contribute to the developmental and evolutionary increase in cortical size and complexity of the human brain. We sequenced mRNA from single human progenitor cells and found that oRG cells preferentially express genes involved in growth factor signaling and self-renewal pathways, suggesting that oRG cells establish a self-sustaining proliferative niche. Using single cell clonal lineage analysis, we found that oRG cells can generate hundreds of daughter neurons, establishing the extensive proliferative and neurogenic capacity of this cell type. Surprisingly, we also discovered that the mTOR signaling pathway, known to promote cell growth and proliferation in a wide variety of cell types, is selectively active in oRG cells. This finding highlights a previously unappreciated cellular pattern of selective vulnerability and may have implications for our understanding of human diseases associated with MTOR pathway mutations, such as autism.

By using novel markers that reveal the morphology of radial glia cell subtypes, we discovered that the radial glial scaffold, which has classically been viewed as a continuous structural framework upon which the cortex develops, becomes a discontinuous pathway entirely constructed by oRG cell fibers. This transformation occurs partway through human brain development and results in a different lineage for upper cortical layer neurons compared to deeper layer neurons. This developmental event may underlie primate-specific features of upper cortical layer neurons that have been related to higher cognitive functions in humans.

Together, our results highlight cellular features of human brain development that are not represented in animal models and may reflect human or primate-specific evolutionary adaptations. These findings also provide a roadmap for interpreting laboratory models of human brain development and evolution.