Contact Mediated Spatial Patterning of the Early Human Neocortex

The neocortex of the human brain mediates our higher-order cognitive functions.  Progress in studying human brain development is limited by evolutionary differences between model organisms and humans. Consequently, the lineage decisions leading the differentiated cell types of the neocortex, neurons and glia, and the signals driving their emergence remain unknown.

Analysis of sequencing data from human fetal tissue suggested the presence of a glial progenitor early in the first trimester of development. These progenitors appeared to arise before neurons, in contrast to mouse, where glia arise after the cessation of neurogenesis.

In-vitro lineage tracing of the progenitors using human embryonic stem cells models revealed a fate decision between glial and neurogenic lineages, prior to neurogenesis. Furthermore, long-term culture revealed their terminal differentiation into astrocytes. These findings suggest that an early glial progenitor is present in human unlike mouse, consistent with reports suggesting that glial development diverged across the mammalian phylogenetic tree.

The differential expression of signaling target genes in the fetal tissue progenitors suggested distinct roles of contact-mediated signaling. Genetic and pharmacological perturbations demonstrated the crucial role these signaling pathways in maintaining the relative spatiotemporal proportions of these cell types.  We discuss the implications of fate-patterning and early glial fate restriction.