Trnp1 Regulates Expansion and Folding of the Mammalian Cerebral Cortex by Control of Radial Glial Fate

Evolution of the mammalian brain encompassed a remarkable increase in size of the cerebral cortex, which includes tangential and radial expansion. However, the mechanisms underlying these key features are still largely unknown. Here, we identified the DNA-associated protein Trnp1 as a regulator of cerebral cortex expansion in both of these dimensions. Gain- and loss-of-function experiments in the mouse cerebral cortex in vivo demonstrate that high Trnp1 levels promote neural stem cell self-renewal and tangential expansion. In contrast, lower levels promote radial expansion, with a potent increase of the number of intermediate progenitors and basal radial glial cells leading to folding of the otherwise smooth murine cerebral cortex. Remarkably, TRNP1 expression levels exhibit regional differences in the cerebral cortex of human fetuses, anticipating radial or tangential expansion. Thus, the dynamic regulation of Trnp1 is critical to control tangential and radial expansion of the cerebral cortex in mammals. [Display omitted] •Trnp1 is a nuclear regulator of radial glial cell fate•Knockdown of Trnp1 results in gyrification (folding) of a naturally smooth brain•Regulation of a single factor orchestrates most characteristics of gyrated brains•Trnp1 associates with DNA and regulates gene expression but has no known motifs Trnp1 is a DNA-associated protein that regulates cortical expansion—both radial and tangential—and gyrification during development. Its expression pattern in the human brain correlates with regional folding levels, and its conservation among mammals suggests that it may have played a role during the evolution of the mammalian brain.