[PS12-2D-3] Neuronal adhesion molecule: L1cam is crucial for radial migration during murine corticogenesis
Brain development is spatiotemporally regulated by genetic and environmental factors. We have investigated pathogenetic mechanisms of abnormal brain development using animal models, which are based on precise analyses of human brain diseases. L1cam (L1), one of the cell adhesion molecules belonging to the immunoglobulin superfamily, plays critical roles in neuronal migration, axon growth, guidance, fasciculation, and synaptic plasticity in the central as well as the peripheral nervous system. A number of X-linked forms of mental retardation have been associated with mutations in the L1 gene, including X-linked hydrocephalus in human. Although model mice with different sites of L1 mutation have been studied, the pathogenetic mechanisms of hydrocephalus and mental retardation still remain unsolved. We herein present experimental evidence showing that L1 is involved in murine neocortical histogenesis. Time-lapse analyses revealed that L1-knockdown (L1-KD) neurons produced by in utero electroporation of shRNA targeting L1 molecules (L1-shRNAs) showed decreased locomotion velocity in the intermediate zone, compared with control neurons. Furthermore, L1-KD neurons showed longer and more undulated leading processes during terminal translocation through the primitive cortical zone (PCZ). The curvature index, a quantitative index for curvilinearity, as well as the length of the leading process, were increased, whereas the somal movement was decreased in L1-KD neurons during terminal translocation in the PCZ. These results suggest that L1 has a role in radial migration of cortical neurons. Finally we propose a hypothetical mechanism of L1-linked hydrocephalus, with reference to corticogenesis.