LGALS3BP modulates local gyrification in the human brain

Basal radial glial cells (bRGs) are neural progenitors enriched in primates and humans and were proposed to contribute to the expansion of neurons during cortical development in gyrencephalic species. Shortly after their generation, bRGs delaminate towards the outer subventricular zone, where they divide multiple times before differentiation. Thus, the regulation of bRGs generation could be essential for the establishment of correct gyrification within the human cortex. Here, we study the role of LGALS3BP, a secreted protein whose RNA expression is enriched in bRGs. By using cerebral organoids, human fetal tissues and mice, we show that manipulation of LGALS3BP regulated bRG generation. Additionally, individuals with unique de novo variants in LGALS3BP demonstrate abnormal gyrification and thickness at multiple sites over their cortex. Single-cell-RNA-sequencing and proteomics reveal the extracellular matrix involvement in the LGALS3BP mediated mechanisms. We find that LGALS3BP is required for bRGs delamination and influences corticogenesis and gyrification in humans.