Lissencephaly and the molecular basis of neuronal migration.

Migration of post-mitotic neurons from the ventricular zone to the cortical plate during embryogenesiscomprises one of the most critical stages in brain development. Deﬁciency of this process often results inmajor brain malformations, including human lissencephaly (smooth brain). Since discovery of the ﬁrstgenetic cause of lissencephaly, deletions of chromosome 17p13.3 in Miller–Dieker syndrome, rapid progressin our understanding of neuronal migration has been made based on advances in both brain imagingtechnology and molecular genetics. This progress has resulted in a new system of classiﬁcation that beganwith pathological descriptions and has evolved to include patterns on brain imaging, causative genes andmost recently the molecular pathways and proposed modes of migration involved. In this review, wesummarize current knowledge regarding ﬁve genes that cause or contribute to human lissencephaly,including LIS1, 14-3-3e, DCX, RELN and ARX. Each of these is associated with a characteristic pattern ofmalformation that involves the cerebral cortex and sometimes other brain structures. Based on detailedgenotype–phenotype analysis, we can now infer the most likely causative gene based on brain imaging andother clinical ﬁndings, and inversely are becoming able to predict clinical severity based on the speciﬁcmutations detected. We also hypothesize, for the ﬁrst time, a relationship between the speciﬁc type oflissencephaly observed and deﬁciency of speciﬁc modes of neuronal migration.INTRODUCTIONMigration of post-mitotic neurons from the ventricular zone toform the cortical plate comprises one of the most critical stagesin brain development. Our understanding of this complexprocess has progressed based on studies of human malformationsand mouse mutants with deﬁcient neuronal migration, particu-larly the malformation known as lissencephaly (LIS) or ‘smooth-brain’. LIS is characterized by a smooth or nearly smoothcerebral surface. It encompasses a spectrum of gyral malforma-tions from complete agyria (absent gyri) to regional pachygyria(broad gyri), and merges with subcortical band heterotopia(SBH). LIS is always associated with an abnormally thick cortex,reduced or abnormal lamination and diffuse neuronal heterotopia(1,2). SBH or ‘double cortex’ consists of circumferential bandsof heterotopic neurons located just beneath the cortex andseparated from it by a thin band of white matter (3,4).Several different types of LIS have been recognized. Themost common type, known as classical LIS (previously type I),has a very thick 10–20mm cortex and no other major brainmalformations. This is the only type associated with SBH. Lesscommon types are associated with agenesis of the corpuscallosum (ACC) or severe cerebellar hypoplasia (5,6).In this paper, we review recent discoveries regarding themolecular mechanisms that regulate or effect neuronalmigration to the cerebral cortex, emphasizing those derivedfrom studies in humans with LIS. Other genes and proteinsidentiﬁed in humans with periventricular nodular heterotopiaor cobblestone complex malformations (previously typeII LIS), or in mouse mutants have been reviewed elsewhere(7–11).HUMAN LISSENCEPHALY GENESTo date, ﬁve genes have been identiﬁed that cause or contributeto LIS in humans: LIS1, 14-3-3e ,DCX RELN and ARX. Theirrespective subtypes and syndromes are shown in Figures 1and 2, and can usually be distinguished based on detailedanalysis of the phenotype as shown in Figure 3.