MPP3 is required for maintenance of the apical junctional complex, neuronal migration, and stratification in the developing cortex.

During mammalian cortical development, division of progenitor cells occurs at the apical ventricular zone. Apical complex proteins and adherens junctions regulate the different modes of division. Here, we have identified the membrane-associated guanylate kinase protein membrane palmitoylated protein 3 (MPP3) as an essential protein for the maintenance of these complexes. MPP3 localizes at the apical membrane in which it shows partial colocalization with adherens junction proteins and apical proteins. We generated Mpp3 conditional knock-out mice and specifically ablated Mpp3 expression in cortical progenitor cells. Conditional deletion of Mpp3 during cortical development resulted in a gradual loss of the apical complex proteins and disrupted adherens junctions. Although there is cellular disorganization in the ventricular zone, gross morphology of the cortex was unaffected during loss of MPP3. However, in the ventricular zone, removal of MPP3 resulted in randomization of spindle orientation and ectopically localized mitotic cells. Loss of MPP3 in the developing cortex resulted in delayed migration of progenitor cells, whereas the rate of cell division and exit from the cell cycle was not affected. This resulted in defects in cortical stratification and ectopically localized layer II-IV pyramidal neurons and interneurons. These data show that MPP3 is required for maintenance of the apical protein complex and adherens junctions and for stratification and proper migration of neurons during the development of the cortex.