A balance of noncanonical Semaphorin signaling from the cerebrospinal fluid regulates apical cell dynamics during corticogenesis

During corticogenesis, dynamic regulation of apical adhesion is fundamental to generate correct numbers and cell identities. While radial glial cells (RGCs) maintain basal and apical anchors, basal progenitors and neurons detach and settle at distal positions from the apical border. Whether diffusible signals delivered from the cerebrospinal fluid (CSF) contribute to the regulation of apical adhesion dynamics remains fully unknown. Secreted class 3 Semaphorins (Semas) trigger cell responses via Plexin-Neuropilin (Nrp) membrane receptor complexes. Here, we report that unconventional Sema3-Nrp preformed complexes are delivered by the CSF from sources including the choroid plexus to Plexin-expressing RGCs via their apical endfeet. Through analysis of mutant mouse models and various ex vivo assays mimicking ventricular delivery to RGCs, we found that two different complexes, Sema3B/Nrp2 and Sema3F/Nrp1, exert dual effects on apical endfeet dynamics, nuclei positioning, and RGC progeny. This reveals unexpected balance of CSF-delivered guidance molecules during cortical development.