Interaction Between Deleted In Colorectal Cancer(DCC)and Disabled1(Dab1)Regulates Neuronal Migration And Lamination In The Neocortex

The laminated structure in mammalian cerebral cortex develops in a stereotypical birth-date-dependent "inside-out" pattern, which is established by neuron migration with sequential changes of migratory mode. Coordinated migration of cortical neurons in the developing and adult cerebral cortex is especially essential for its proper function, and migration defects can cause neurological and psychiatric diseases. Reelin-Dab1 signaling pathway is significant for neocortical "inside-out" sequential lamination, but the molecular mechanisms of its action are poorly defined. It has been reported that the outmost region of cortical plate, which is named primitive cortical zone (PCZ), has several histologically distinct features and its establishment depends on the existence of Dab 1. PCZ is also a unique environment, beneath which the migratory mode change from locomotion to terminal translocation.DCC (Deleted in Colorectal Cancer) is a transmembrane molecule of Ig superfamily that serves as a receptor protein for the guidance signaling cue Netrin-1 to regulate axon attraction. DCC has also been proved to meditate cell proliferation, associate with protein synthesis machinery and regulate translation recently. However, we are fascinated by how this signaling pathway makes neocortex develop into such an organized structure. Here, we show that there is a serious laminar displacement in DCC mutant mouse-DCCkanga (A spontaneous recessive mutant mouse that lacks the P3-domain of DCC). In addition, Loss of DCC P3-domain in DCCkangaresults in severe histological and morphological defects in PCZ of neocortex. Further, whereas DCC-knockdown (KD) neurons could reach the beneath the PCZ, they failed to enter the PCZ after three days electroporation, suggesting that DCC is required for migration of cortical neurons in cortical plate. Mechanistically, we show that Dab1 binds to the third intracellular P3 domain of DCC, and the Dab1 phosphorylation increased in DCCkanga. Together, our results indicate that neuronal migration in the developing cortex requires the DCC-Dabl interaction.