Lissencephaly: mechanistic insights from animal models and potential therapeutic strategies

Abstract

Lissencephaly is a severe human neuronal migration defect characterized by a smooth cerebral surface, mental retardation and seizures. The two most common genes mutated in patients with lissencephaly are LIS1 and DCX. LIS1 was the first gene cloned that was important for neuronal migration in any organism, and heterozygous mutations or deletions of LIS1 are found in the majority of patients with lissencephaly, while DCX mutations were found in males with X-linked lissencephaly. In this review, we will discuss how an understanding of the molecular and cellular pathways disrupted in model organisms with Lis1 and Dcx mutations or knock-down not only provide insights into the normal processes of neuronal migration, including neurogenesis, but they also may lead to potential novel therapeutic strategies for these severe cortical malformations.

Fig 1

Neurogenesis in (A) neuroepithelial stem cells (NESC) and (B) radial glial progenitor cells (RGPC). In NESC, nuclei undergo interkinetic nuclear migration from apical to basal surfaces, and divide symmetrically and vertically to produce NESCs. In RGPCs, interkinetic nuclear migration occurs only in the ventricular zone (VZ). At the ventricular zone, the RGPCs divide mostly vertically, but this division can be symmetric (S-M) to produce two RGPCs, or asymmetric (AS-M) to produce one RGPC and either one neuron or one basal progenitor (BP). This BP moves to the subventricular zone at the border of the VZ and intermediate zone (IZ), where it divides once symmetrically and horizontally to produce two neurons. Neurons produced by either of these two ways migrate into the cortical plate (CP), where they set up the cortical layers in an inside-out fashion.

Fig. 2

The LIS1/NDE/dynein complex, conserved from Aspergillus through mammals. LIS1 interacts directly with NDE1 and NDEL1, which interact with the cytoplasmic dynein light (CDLC) and heavy (CDHC) chains to regulate centrosomal protein localization and function as well as microtubule dynamics. These interactions are critical for nuclear movements and neuronal migration. NDEL1 is phosphorylated by two different mitotic kinases: CDK5 with its required coactivator p35 phosphorylates NDEL1 on three sites (S198, T219, S231); and Aurora A kinase (AURKA) phosphorylates NDEL1 on S251. CDK5-phosphorylated NDEL1 binds to 14-3-3ε, which protects NDEL1 from dephosphorylation, perhaps by phosphatase 4 (PP4) or phosphatase 2A (PP2A), since NDEL1 binds to the PP2A subunit PR65α. LIS1 also interacts with IQGAP and CLIP170.

Fig. 3

LIS1 binding partipates in the anterograde transport of dynein via kinesin motors to the surface of the cell (cortex). At the cell cortex, the dynein is unloaded at the plus-end of microtubules allowing dynein to attach to the cortex while LIS1 is degraded via calpain-dependent proteolysis.