title: Global developmental gene expression and pathway analysis of normal brain development and mouse models of human neuronal migration defects.
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.
authors.affiliation: Department of Pediatrics and Institute for Human Genetics, School of Medicine, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Tiziano
authors.initials: T
authors.lastname: Pramparo
authors.forename: Ondrej
authors.initials: O
authors.lastname: Libiger
authors.forename: Sonia
authors.initials: S
authors.lastname: Jain
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: Yong Ha
authors.initials: YH
authors.lastname: Youn
authors.forename: Shinji
authors.initials: S
authors.lastname: Hirotsune
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Schork
authors.forename: Anthony
authors.initials: A
authors.lastname: Wynshaw-Boris
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000235:genetics / Q000378:metabolism; D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000196:embryology / Q000254:growth & development / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion; D002453:Cell Cycle; D002465:Cell Movement; D016764:Cell Polarity / Q000235:genetics; D003599:Cytoskeleton / Q000378:metabolism; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction; D013569:Synapses / Q000502:physiology; D015854:Up-Regulation
chemical_list: D048948:14-3-3 Proteins; D002352:Carrier Proteins; C000714328:DCX protein, human; C000714847:Dcx protein, mouse; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D008869:Microtubule-Associated Proteins; C486015:Ndel1 protein, mouse; D009479:Neuropeptides; D011493:Protein Kinase C; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C513190:Pafah1b1 protein, mouse