Abstract
Heterozygous LIS1 mutations are the most common cause of human lissencephaly, a human neuronal migration defect, and DCX mutations are the most common cause of X-linked lissencephaly. LIS1 is part of a protein complex including NDEL1 and 14-3-3ε that regulates dynein motor function and microtubule dynamics, while DCX stabilizes microtubules and cooperates with LIS1 during neuronal migration and neurogenesis. Targeted gene mutations of Lis1, Dcx, Ywhae (coding for 14-3-3ε), and Ndel1 lead to neuronal migration defects in mouse and provide models of human lissencephaly, as well as aid the study of related neuro-developmental diseases. Here we investigated the developing brain of these four mutants and wild-type mice using expression microarrays, bioinformatic analyses, and in vivo/in vitro experiments to address whether mutations in different members of the LIS1 neuronal migration complex lead to similar and/or distinct global gene expression alterations. Consistent with the overall successful development of the mutant brains, unsupervised clustering and co-expression analysis suggested that cell cycle and synaptogenesis genes are similarly expressed and co-regulated in WT and mutant brains in a time-dependent fashion. By contrast, focused co-expression analysis in the Lis1 and Ndel1 mutants uncovered substantial differences in the correlation among pathways. Differential expression analysis revealed that cell cycle, cell adhesion, and cytoskeleton organization pathways are commonly altered in all mutants, while synaptogenesis, cell morphology, and inflammation/immune response are specifically altered in one or more mutants. We found several commonly dysregulated genes located within pathogenic deletion/duplication regions, which represent novel candidates of human mental retardation and neurocognitive disabilities. Our analysis suggests that gene expression and pathway analysis in mouse models of a similar disorder or within a common pathway can be used to define novel candidates for related human diseases.
Highlights
Neuronal migration defects such as lissencephaly are an important cause of mental retardation and severe epilepsy in humans, and many of the genes responsible for these conditions have been identified, including LIS1 and DCX [1,2,3,4]
Our results provide new insights into the pathways and biological processes that regulate normal brain development and that are altered in mouse mutants of human neuronal migration defects, and they suggest a genomic approach to use gene expression analysis of mouse models of human genetic disease to identify candidate genes for related disorders, such as mental retardation and epilepsy
We investigated global gene expression of wild-type (WT) mice and four mouse models for human neuronal migration defects (Lis1, Dcx, Ywhae and Ndel1) at three developmental stages (E14, P0 and P14) following a three-step strategy (Figure S1) to define common and different gene expression signatures as well as dysregulated genes
Summary
Neuronal migration defects such as lissencephaly are an important cause of mental retardation and severe epilepsy in humans, and many of the genes responsible for these conditions have been identified, including LIS1 and DCX [1,2,3,4]. LIS1 is part of a complex that includes NDEL1 [6,7] and 14-3-3 epsilon [8] This complex is essential for the regulation and localization of cytoplasmic dynein (light and heavy chains), centrosomal protein localization and function as well as microtubule dynamics (for review, see [9,10,11]). These interactions are critical for nuclear movements and neuronal migration. Similar to LIS1, mutations of DCX are the most common cause of X-linked lissencephaly in humans [5]. There is some evidence that DCX either directly interacts with the proteins of the LIS1 complex, and genetic interactions between Lis and Dcx have been demonstrated [13,14]
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