Kif2C safeguards radial glial integrity to prevent cortical malformation

Radial glial cells (RGCs) generate cortical neurons and guide radial neuronal migration, yet how microtubule (MT) regulators coordinate progenitor maintenance, mitotic fidelity, and cortical architecture remains unclear. Here, we identify the MT depolymerase Kif2C/MCAK as an essential regulator of RGC integrity with relevance to human neurodevelopmental disorders. Kif2C is enriched in developing cortical RGCs and localizes to radial fibers, basal endfeet, and mitotic structures. Acute Kif2C depletion in embryonic mouse cortices disrupts RG fiber organization, impairs neuronal migration, reduces the RGC pool, and induces mitotic defects, chromosome segregation errors, DNA damage, and cell-cycle arrest. Kif2C-deficient cortices further exhibit focal pial basement membrane disruption and neuronal overmigration, resulting in a cobblestone-like cortical malformation. We identify two individuals with neurodevelopmental disorders carrying rare deleterious KIF2C variants and show that a patient-derived truncating variant fails to rescue Kif2C-deficient cortical phenotypes, implicating KIF2C dysfunction in human neurodevelopmental disorders. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=181 SRC="FIGDIR/small/726143v1_ufig1.gif" ALT="Figure 1"> View larger version (67K): org.highwire.dtl.DTLVardef@1970844org.highwire.dtl.DTLVardef@9fe29eorg.highwire.dtl.DTLVardef@d72ddcorg.highwire.dtl.DTLVardef@103f729_HPS_FORMAT_FIGEXP M_FIG C_FIG