SRP124509 PRJNA417495 GSE106640 Extracellular matrix components HAPLN1, lumican and collagen I cause hyaluronic acid-dependent folding of the developing human neocortex Neocortical expansion, thought to underlie the cognitive traits unique to humans, is accompanied by cortical folding. This folding starts around gestational week (GW) 20, but what causes it remains largely unknown. Extracellular matrix (ECM) has been previously implicated in neocortical expansion. Here, we investigate the potential role of ECM in the formation of neocortical folds. We focus on three specific ECM components localized in the human fetal cortical plate (CP): hyaluronan and proteoglycan link protein 1, lumican and collagen I (collectively, HLC). Addition of HLC to cultures of human fetal neocortex (11-22 GW) caused local changes in tissue stiffness and induced CP folding. HLC-induced folding increased CP hyaluronic acid (HA), required the HA-receptor CD168 and downstream ERK signaling, and was prevented/reversed by hyaluronidases. HLC did not induce CP folding in cultures of developing mouse and ferret neocortex. Together, our data suggest a human-specific role of ECM in neocortical folding. Overall design: Gene expression profiles of the cortical plate of fetal human neocortex after 16 hours of control or HLC-treatment were generated by RNA-seq and analyzed. The cortical plate was isolated by laser capture microdissection. GSE106640 pubmed 30078576