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Global developmental gene expression and pathway analysis of normal brain development and mouse models of human neuronal migration defects

ABSTRACT: Proper cortical development relies on the balance of neuronal migration and proliferation. We investigated the gene expression differences of mouse knock-outs for Lissencephaly in humans. 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. We investigated the developing brain of 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.

ORGANISM(S): Mus musculus

SUBMITTER: Tiziano Pramparo

PROVIDER: E-GEOD-35366 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Global developmental gene expression and pathway analysis of normal brain development and mouse models of human neuronal migration defects

Project description:Proper cortical development relies on the balance of neuronal migration and proliferation. We investigated the gene expression differences of mouse knock-outs for Lissencephaly in humans. 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.

2012-01-26 | GSE35366 | GEO

Transient knockdown of LIS1 results in seizures, differential gene expression and a neuronal migration disorder in developing zebrafish

Project description:Mutation or deletion of LIS1 (Lissencephaly-1) underlies classical lissencephaly, a migration disorder resulting in brain malformation, epilepsy and mental retardation. Orthologues for LIS1 genes (lis1a and lis1b) are ubiquitously expressed in developing zebrafish larvae, but the functional consequences of Lis1 knockdown are unknown. Here we used lis1-specific morpholino oligonucleotides (MOs, targeting protein translation or mRNA splicing, respectively) to transiently knockdown Lis1 expression in zebrafish. Injection of lis1 MOs resulted in morphological changes including microcephaly. At four days post-fertilization, lis1 morphants exhibited spontaneous convulsive behavior and abnormal large-amplitude electrographic discharge resembling that seen in acute and genetic zebrafish models of epilepsy. Abnormal brain development and neuronal migration defects were observed when lis1 MO injections were made into fluorescent reporter lines demarcating interneuron distribution (Dlx5a/6a:GFP) and brain structure (GBT0133:mRFP). Microarray analysis for ~44,000 Danio rerio transcripts identified 215 up-regulated and 160 down-regulated genes. Quantitative PCR and whole-mount in situ hybridization were used to validate these results for twenty and seven genes, respectively. These findings in a simple vertebrate model reproducing neuroanatomical and epileptic hallmarks of the human condition represent a novel approach to the study of childhood seizure disorders associated with a single gene mutation 4 WT samples (sample= 10 pooled larvae) and 4 Lis1Morphants slight phenotype (sample= 10 pooled larvae) were collected at 4dpf (days post fertilization). The morphants were selected based on phenotype and seizure behavior. Both groups of fish derived from same pools of eggs

2013-06-15 | E-GEOD-47952 | biostudies-arrayexpress

Transient knockdown of LIS1 results in seizures, differential gene expression and a neuronal migration disorder in developing zebrafish

2013-06-15 | GSE47952 | GEO

LIS1 RNA-binding orchestrates the mechanosensitive properties of embryonic stem cells in AGO2-dependent and independent ways

Project description:Lissencephaly-1 (LIS1) is associated with neurodevelopmental diseases and is known to regulate the molecular motor cytoplasmic dynein activity. Here we show that LIS1 is essential for the viability of mouse embryonic stem cells (mESCs), and it governs the physical properties of these cells. LIS1 dosage substantially affects gene expression, and we uncovered an unexpected interaction of LIS1 with RNA and RNA-binding proteins, most prominently the Argonaute complex. We demonstrate that LIS1 overexpression partially rescued the extracellular matrix (ECM) expression and mechanosensitive genes conferring stiffness to Argonaute null mESCs. Collectively, our data transforms the current perspective on the roles of LIS1 in post-transcriptional regulation underlying development and mechanosensitive processes.

2023-05-04 | GSE198390 | GEO

Mutations in the microtubule-associated protein Eml1 lead to ectopic progenitors and heterotopia formation during cortical development in mouse and human

Project description:Neuronal migration disorders such as lissencephaly and subcortical band heterotopia (SBH) are associated with epilepsy and intellectual disability. Doublecortin (DCX), LIS1 and alpha1-tubulin (TUBA1A), are mutated in these disorders, however corresponding mouse mutants do not show heterotopic neurons in the neocortex. On the other hand, the spontaneously arisen HeCo mouse mutant displays this phenotype. The study of this model reveals novel mechanisms of heterotopia formation. While, HeCo neurons migrate at the same speed as WT, abnormally distributed dividing progenitors were found throughout the cortical wall from E13. Through genetic studies we identified Eml1 as the mutant gene in HeCo mice. No full length transcripts of Eml1 were identified due to a retrotransposon insertion in an intron. Re-expression of Eml1, coding for a microtubule-associated protein, rescues the HeCo progenitor phenotype. We further show that EML1 is mutated in giant ribbon-like heterotopia in human. Our data link abnormal spindle orientations, ectopic progenitors and severe heterotopia in mouse and human. 16 samples analyzed corresponding to 8 wild type brain and 8 HeCo mutant brain

2014-05-25 | E-GEOD-56907 | biostudies-arrayexpress

Mutations in the microtubule-associated protein Eml1 lead to ectopic progenitors and heterotopia formation during cortical development in mouse and human

2014-05-25 | GSE56907 | GEO

DCX knockout ferret disentangles cellular landscape of lissencephaly syndrome and novel functions of DCX in neural progenitors

Project description:Lissencephaly (LIS) represents a range of gene-associated brain abnormalities characterized by a smooth cortical surface (due to the absence or reduction of gyri and sulci) in humans. This condition manifests through various symptoms such as seizures, muscle spasms, developmental delays, cognitive impairments, and learning discrepancies, etc.1-3 To date, nearly twenty gene mutations related to lissencephaly have been identified, with DCX and LIS1 being the most commonly reported risk genes in humans1-5. Our understanding of this disease remains limited due to the absence of suitable models that accurately represent human phenotypes. In this study, we conducted a comprehensive examination of the phenotypes, cytoarchitecture, and cellular profiles of the neocortex in DCX knockout ferrets we generated previously 6. Our findings indicate that the DCX knockout ferrets effectively replicate the morphological and pathological phenotypes observed in human patients. Furthermore, we discovered a novel function of DCX in neural progenitor cells (NPCs), that DCX inhibits the proliferation of NPCs and regulates the extension of radial glial fibers, which serve as a migration scaffold for neurons. We also present evidence suggesting that inhibitory neurons pair with their excitatory counterparts in a subtype-specific manner during their migration and distribution in the neocortex, which was also dysregulated in DCX knockout ferrets.

2023-08-04 | GSE239781 | GEO

Wild type vs. Nova2 KO mouse E14.5 cortex RNA

Project description:To assess the requirement of Nova2 for alternative processing of RNA in the developping brain. Neuronal migration leads to a highly organized laminar structure in the mammalian brain and its mis-regulation causes lissencephaly, behavioral and cognitive defects. Reelin signaling, mediated in part by a key adaptor, disabled-1 (Dab1), plays a critical but incompletely understood role in this process. We found that the neuron-specific RNA binding protein Nova2 regulates neuronal migration in late-generated cortical and Purkinje neurons. An unbiased HITS-CLIP and exon junction array search for Nova-dependent RNAs at E14.5 focused on components of the reelin pathway revealed only one candidate—an alternatively spliced isoform of Dab1 (Dab1.7bc). In utero electroporation demonstrated that Dab1.7bc was sufficient to induce neuronal migration defects in wild-type mice and exacerbate defects when Dab1 levels were reduced, while Dab1 overexpression mitigates defects in Nova2-null mice. Thus Nova2 regulates an RNA switch controlling the ability of Dab1 to mediate neuronal responsiveness to reelin signaling and neuronal migration, suggesting new links between splicing regulation, brain disease and development. Keywords: Comparative analysis RNA from the cortex of 3 wild type and 3 Nova2 KO E14.5 cortex. One array per biological replicate.

2010-07-07 | E-GEOD-22758 | biostudies-arrayexpress

Wild type vs. Nova2 KO mouse E14.5 cortex RNA

2010-07-07 | GSE22758 | GEO

Danio rerio

Project description:Transient knockdown of LIS1 results in seizures, differential gene expression and a neuronal migration disorder in developing zebrafish

| PRJNA208438 | ENA

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