Figure 3.

Roles of LIS-associated genes in association with microtubule function and neuronal migration/organization. (I) Mutations in tubulin isotypes disrupt the formation of normal heterodimers of α- and β-tubulin polypeptides, affecting the structural stability and function of microtubules; (II) kinesins and (III) dyneins are microtubule motor proteins that power directional movement along microtubules. Lissencephaly (LIS)-related genes that encode these motor proteins include KIF2A, KIF5C and DYNC1H1; (IV) the LIS1 gene encodes the LIS1 protein which is an adaptor for the microtubule-motor dynein that allows dynein to remain attached to microtubules for longer periods of time; (V) the mammalian NudE homologues (NDE1 and NDEL1) are required for the targeting of LIS1 to the dynein complex. It also releases the blocking effect of LIS1 on cytoplasmic dynein; (VI) DCX protein binds directly to microtubules to stabilize and promote polymerization, facilitates the formation of the microtubule cage around the nucleus, as well as stabilizes microtubules in the leading process of the migrating neuron; (VII) the Reelin signalling pathway aids in the regulation of neuronal migration and positioning, generating the “inside first-outside last” configuration of the 6-layer cortex; (VIII) CDK5 regulates the binding and assembly of LIS1-dynein complex as well as the direct binding of DCX to microtubules; (IX) the ARX gene encodes the ARX protein (a transcription factor) which regulates genes that play crucial roles in tangential migration of GABAergic interneurons into the cortical plate; (X) ACTB and ACTG1 encode β- and γ-actin. The interaction between microtubules and cytoplasmic actin plays an important role in neuronal migration. DCX protein allows “cross-talk” between microtubules and cytoplasmic actins; (XI) the CRADD gene is a recently discovered LIS-associated gene. Its role in neuronal migration and hence development of LIS is still unclear and needs further investigation. MCD, malformations of cortical development.