NEUROG2regulates a human-specific neurodevelopmental gene regulatory program

Abstract

ABSTRACTUnique hallmarks of human neocortical development include slower rates of neurogenesis and the establishment of an extracellular matrix-rich, outer-subventricular zone that supports basal neural progenitor cell expansion. How gene regulatory networks have evolved to support these human-specific neurodevelopmental features is poorly understood. Mining single cell data from cerebral organoids and human fetal cortices, we found thatNEUROG2expression is enriched in basal neural progenitor cells. To identify and purifyNEUROG2-expressing cells and trace their short-term lineage, we engineered twoNEUROG2-mCherryknock-in human embryonic stem cell lines to produce cerebral organoids. Transcriptomic profiling of mCherry-high organoid cells revealed elevated expression ofPPP1R17, associated with a fast-evolving human-accelerated regulatory region, oligodendrocyte precursor cell and extracellular matrix-associated gene transcripts. Conversely, only neurogenic gene transcripts were enriched in mCherry-high cortical cells fromNeurog2:mCherryknock-in mice. Finally, we show thatNeurog2is sufficient to inducePpp1r17, which slows human neural progenitor cell division, andCol13a1, an extracellular matrix gene, in P19 cells.NEUROG2thus regulates a human neurodevelopmental gene regulatory program implicated in supporting a pro-proliferative basal progenitor cell niche and tempering the neurogenic pace.SUMMARY STATEMENTTranscriptomic analyses ofNEUROG2-mCherryknock-in human embryonic stem cell-derived cerebral organoids reveal a link betweenNEUROG2and extracellular matrix remodeling during human cortical development.