LIS1 and DCX: Implications for Brain Development and Human Disease in Relation to Microtubules

Abstract

Proper lamination of the cerebral cortex requires the orchestrated motility of neurons from their place of birth to their final destination. Improper neuronal migration may result in a wide range of diseases, including brain malformations, such as lissencephaly, mental retardation, schizophrenia, and autism. Ours and other studies have implicated that microtubules and microtubule-associated proteins play an important role in the regulation of neuronal polarization and neuronal migration. Here, we will review normal processes of brain development and neuronal migration, describe neuronal migration diseases, and will focus on the microtubule-associated functions of LIS1 and DCX, which participate in the regulation of neuronal migration and are involved in the human developmental brain disease, lissencephaly.

Figure 1

Schematic presentation of progenitors in the developing cerebral cortex. Radial glia cells (RGCs) extend their processes from the ventricular zone (VZ) to the pial surface. These cells proliferate in a symmetrical fashion to produce additional RGC or asymmetrically to produce a progenitor and a multipolar cell (MPC), which may be either a postmitotic neuron or an intermediate progenitor (IP), which can further divide in the subventricular zone. The VZ contains additional short neuronal progenitors (SNP). In the SVZ and the outer SVZ (OSVZ), an additional type of progenitors was described, basal radial glia (BRG), which lack the connection to the ventricle. A bipolar migrating neuron (MN) is moving towards the intermediate zone (IZ).

Figure 2

Schematic presentation of interkinetic nuclear movements in the ventricular zone (VZ). Nuclei of RGC are found at the upper surface of the VZ during S phase (S). The nuclei of the cells undergoing mitosis (M phase) are located close to the ventricle, where they complete anaphase (A) and telophase (T). Nuclei in G1 and G2 phases are found in intermediate positions.

Figure 3

Schematic presentation of migratory routes of excitatory and inhibitory neurons in the developing brain (adapted from a review by Tan and Shi, WIREs Dev Biol 2012. doi: 10.1002/wdev.88). Inhibitory neurons are shown in the left side. Most of the GABAergic neurons are born in the ventral part of the telencephalon, in the subpallium, and more specifically in the medial ganglionic eminence (MGE) and the lateral ganglionic eminence (LGE), in the subpallial septum, and the embryonic preoptic area (POA), and they migrate in a tangential way to the cortex. St: striatum; LP: lateral pallium; H: hippocampus.