Lissencephaly and the molecular basis of neuronal migration

Abstract

Migration of post-mitotic neurons from the ventricular zone to the cortical plate during embryogenesis comprises one of the most critical stages in brain development. Deficiency of this process often results in major brain malformations, including human lissencephaly (smooth brain). Since discovery of the first genetic cause of lissencephaly, deletions of chromosome 17p13.3 in Miller-Dieker syndrome, rapid progress in our understanding of neuronal migration has been made based on advances in both brain imaging technology and molecular genetics. This progress has resulted in a new system of classification that began with pathological descriptions and has evolved to include patterns on brain imaging, causative genes and most recently the molecular pathways and proposed modes of migration involved. In this review, we summarize current knowledge regarding five genes that cause or contribute to human lissencephaly, including LIS1, 14-3-3 epsilon, DCX, RELN and ARX. Each of these is associated with a characteristic pattern of malformation that involves the cerebral cortex and sometimes other brain structures. Based on detailed genotype-phenotype analysis, we can now infer the most likely causative gene based on brain imaging and other clinical findings, and inversely are becoming able to predict clinical severity based on the specific mutations detected. We also hypothesize, for the first time, a relationship between the specific type of lissencephaly observed and deficiency of specific modes of neuronal migration.