- Neuronal migration mechanisms in development and disease.
- A novel sex determination system in a close relative of the house mouse.
- Nup153 and megator define transcriptionally active regions in the Drosophila genome.
Classical Lissencephaly (LIS) is a diffuse cortical malformation resulting from incomplete neuronal migration during early brain development. It encompasses a continuous spectrum of malformations from complete agyria to variable degrees of agyria and pachygyria to subcortical band heterotopia (SBH) only. Clinical manifestations range from profound mental retardation, intractable epilepsy, spasticity and reduced longevity to milder forms with infrequent seizures and intellectual disability only. The clinical severity generally correlates with the degree of agyria and cortical thickening. Lissencephaly may occur as an isolated brain malformation in patients with isolated lissencephaly sequence (ILS) or as a component of the contiguous gene deletion disorder known as Miller-Dieker syndrome (MDS) caused by large deletions of chromosome 17p13.3. This syndrome is characterized by facial dysmorphism and cardiac anomalies and accounts for 40% of lissencephaly cases.
Mutations in the LIS1, DCX, RELN, ARX and the TUBA3/TUBA1A genes are known to cause lissencephaly in humans. LIS1 is the alpha subunit of the 1B isoform of the acetylhydrolase of the platelet activating factor, doublecortin (DCX) is a microtubule associated protein, reelin (RELN) is a secreted molecule, aristaless (ARX) is a homeodomain containing protein and TUBA3/TUBA1A is a member of the alpha-tubulin family. The type of lissencephaly observed in the patients is quite different in these five cases and we are going to describe them further (reviewed in Guerrini et Marini, 2006).
The most frequent cause of lissencephaly is the presence of mutations in the LIS1 gene (Reiner et al., 1993) or the DCX gene (Gleeson et al., 1998 ; des Portes et al., 1998). The main difference between these two types of lissencephaly concerns the topographic involvement : whereas mutations in LIS1 are causing a more severe phenotype in the posterior regions of the cerebral cortex, DCX mutations and causing anterior lesions. Recent studies have shown that these two proteins are able to interact with microtubules and to function with the proteins in the centrosome (gamma-tubulin and dynein). The doublecortin protein is a member of the MAP (microtubule associated protein) protein family which could play a role in the stabilisation of this cellular structure which is essential in order for a cell to migrate. It is also known today that the LIS1 and DCX proteins are able to interact together in vitro. However, it is still unknown how a defect in one of these two proteins is leading to the cerebral phenotype which is observed in patients (reviewed in Gupta et al. 2002).
The lissencephaly phenotype caused by mutations in the RELN gene (Hong et al., 2000) is less severe. It is usually described as pachygyria rather than agyria. In addition, the patients present a cerebellar hypoplasia which is not found in patients with mutations in the LIS1 or DCX genes. The RELN gene has been cloned in humans after the mouse gene had been extensively characterized (D’Arcangelo et al., 1995). The mouse Reelin gene is the gene which is abnormal in the reeler mouse mutant. Reeler mice have gait problems and defects in cortical lamination (in the neocortex and the cerebellum). The reelin protein is large and expressed in the marginal zone of the neocortex and in the cerebellum. This protein is a ligand for the receptor of very low density lipoproteins (VLDLR) and the apolipoprotein E receptor (ApoER2) (D’Arcangelo et al., 1999). Genetic studies have shown that if these two receptors are abnormal in mice, the resulting phenotype is very similar to the reeler phenotype (Trommsdorff et al., 1999). Additional genetic studies have shown that another mouse model, the scrambler mouse, was caused by mutations in the Dab-1 gene which encodes a cytoplasmic protein able to specifically recognize the VLDLR and ApoER2 receptors. It is currently known that these two receptors are able to induce the phosphorylation of Dab-1 upon binding of reelin or to induce a proteolytic cleavage mediated by reelin (which is thought to have a protease activity). If Dab-1 is prevented from being phosphorylated in vivo, a neuronal migration disorder is observed in the mutant mice. The biochemical and genetic studies which have been conducted in this case clearly demonstrate the very important interest of studying the natural perturbations of neuronal migration to identify signalling pathways used in normal migration processes (reviewed in Tissir et Goffinet, 2003).
ARX was identified as a lissencephaly gene in 2002 (Stromme et al., 2002). Mutations in the ARX gene are causing a lissencephaly with frontal predominance. The type of lissencephaly is rather different than the one which is observed when LIS1 or DCX are mutated (especially concerning cortex thickness). Mutations in the ARX gene can cause a lissencephaly phenotype associated with corpus callosum agenesis and/or ambiguous genitalia. A very large phenotypic spectrum is associated with ARX mutations but this observation is not currently explained. ARX is encoding a homeodomain protein which is expressed predominantly in the adult and foetal brain and in the skeletal muscle. In mice, the Arx gene is highly expressed in the frontal cortex, in good agreement with the « frontal » phenotype observed in humans. The ARX protein is thought to be a transcriptional repressor although it was not demonstrated. The LIS1 and RELN genes are located on autosomes (17p13 and 7q22 respectively). On the other hand, the DCX and ARX genes are located on the human X chromosome. This means that the mode of inheritance of lissencephalies is directly influenced by sex. Women can be unaffected carriers or mildly affected (subcortical band heterotopia for the carriers of DCX mutations for instance). Knowing the molecular defect at fault in such phenotypes is thus of crucial importance because it will directly impact the type of genetic counselling provided to the families.
The most recently identified lissencephaly gene is the tubulin alpha-1 gene called TUBA3 or TUBA1A (Keays et al. 2007). This gene was identified after the cloning of the mouse homolog in a mouse model displaying an abnormal lamination of the hippocampus. Mutations in this gene are transmitted according to autosomal dominance. Besides lissencephaly, the patients show abnormalities of the corpus callosum and of the brainstem (Poirier et al. 2007).