A Human-Specific De Novo Gene Promotes Cortical Expansion and Folding.

Abstract

Newly originated de novo genes have been linked to the formation and function of the human brain. However, how a specific gene originates from ancestral noncoding DNAs and becomes involved in the preexisting network for functional outcomes remains elusive. Here, a human-specific de novo gene, SP0535, is identified that is preferentially expressed in the ventricular zone of the human fetal brain and plays an important role in cortical development and function. In human embryonic stem cell-derived cortical organoids, knockout of SP0535compromises their growth and neurogenesis. In SP0535transgenic (TG) mice, expression of SP0535induces fetal cortex expansion and sulci and gyri-like structure formation. The progenitors and neurons in the SP0535TG mouse cortex tend to proliferate and differentiate in ways that are unique to humans. SP0535TG adult mice also exhibit improved cognitive ability and working memory. Mechanistically, SP0535interacts with the membrane protein Na+ /K+ ATPase subunit alpha-1 (ATP1A1) and releases Src from the ATP1A1-Src complex, allowing increased level of Src phosphorylation that promotes cell proliferation. Thus, SP0535is the first proven human-specific de novo gene that promotes cortical expansion and folding, and can function through incorporating into an existing conserved molecular network.