DCX knockout ferret disentangles cellular landscape of lissencephaly syndrome and novel functions of DCX in neural progenitors
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ABSTRACT:
PROVIDER: PRJNA1000958 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25488142_1.fastq.gz | Fastqsanger.gz | |||
| SRR25488142_2.fastq.gz | Fastqsanger.gz | |||
| SRR25488143_1.fastq.gz | Fastqsanger.gz | |||
| SRR25488143_2.fastq.gz | Fastqsanger.gz |
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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
Project description:The human cerebral cortex depends for its normal development and size on a precisely controlled balance between self-renewal and differentiation of diverse neural progenitor cells. Specialized progenitors that are common in humans, but virtually absent in rodents, called â??outer radial gliaâ?? (ORG), have been suggested to be crucial to the evolutionary expansion of the human cortex. We combined cell type-specific sorting with transcriptome-wide RNA-sequencing to identify genes enriched in human ORG, including targets of the transcription factor Neurogenin, and previously uncharacterized, evolutionarily dynamic, long noncoding RNAs. Single-cell transcriptional profiling of human, ferret, and mouse progenitors showed that more human RGC co-express proneural Neurogenin targets than in ferret or mouse, suggesting greater self-renewal of neuronal lineage-committed progenitors in humans. Finally, we show that activating the Neurogenin pathway in ferret RGC promotes delamination and outward migration. Thus, we find that the abundance of human ORG is paralleled by increased transcriptional heterogeneity of cortical progenitors. Three biological replicates of human late mid-fetal cortex (18 to 19 weeks of gestation) were dissociated and immunolabeled. Apical and outer radial glial cells were purified by FACS and compared to an immunonegative population, predominantly neurons.
2015-02-24 | E-GEOD-66217 | biostudies-arrayexpress
Project description:The human cerebral cortex depends for its normal development and size on a precisely controlled balance between self-renewal and differentiation of diverse neural progenitor cells. Specialized progenitors that are common in humans, but virtually absent in rodents, called ‘outer radial glia’ (ORG), have been suggested to be crucial to the evolutionary expansion of the human cortex. We combined cell type-specific sorting with transcriptome-wide RNA-sequencing to identify genes enriched in human ORG, including targets of the transcription factor Neurogenin, and previously uncharacterized, evolutionarily dynamic, long noncoding RNAs. Single-cell transcriptional profiling of human, ferret, and mouse progenitors showed that more human RGC co-express proneural Neurogenin targets than in ferret or mouse, suggesting greater self-renewal of neuronal lineage-committed progenitors in humans. Finally, we show that activating the Neurogenin pathway in ferret RGC promotes delamination and outward migration. Thus, we find that the abundance of human ORG is paralleled by increased transcriptional heterogeneity of cortical progenitors.
2015-02-24 | GSE66217 | GEO
Project description:The domestic ferret (Mustela putorius furo) has been used as animal model for decades, largely because its susceptibility to infection with a large number of pathogens such as influenza virus, SARS Corona virus and Canine distemper virus. Despite its importance for biomedical research, little is known about the genome of the M. Furo. The number of reagents for molecular and immunological analysis is thus restricted. To circumvent this, we present here a parallel sequencing effort to produce an extensive EST dataset derived from a normalized ferret cDNA library made from mRNA from ferret blood, liver, lung, spleen and brain. We produced more than 500000 sequence reads that were assembled into over 15000 partial ferret transcripts. These ESTs were combined with the available ferret sequences in the GenBank to develop a ferret specific microarray platform. Using this array, we detected tissue specific expression patterns which were confirmed by quantitative real time PCR assays and comparison to orthologous transcription profiles of mouse and human. We also present a set of 41 ferret transcript with even transcription profile across the tested tissues, indicating their usefulness as housekeeping genes. This study paves way for development of additional reagents for analysis of the ferret model. Three biological replicates of blood, lung, spleen, liver and brain was hybridized to the ferret specific microarray.
2010-09-13 | E-GEOD-19398 | biostudies-arrayexpress
Project description:Characterization of Ferret Microbiota
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Project description:Echinoderm microtubule (MT)-associated protein-like 1 (Eml1) is mutated in the HeCo mouse, which exhibits subcortical band heterotopia (SBH), a developmental malformation of the cerebral cortex. EML1 mutations are also found in human patients affected by severe ribbon-like heterotopia, associated with epilepsy and intellectual disability (1). Neural progenitors in the ventricular zone (VZ) of the developing cerebral cortex undergo precisely regulated divisions, and mitotic perturbations contribute to pathological mechanisms (2). Eml1 is expressed in the mouse VZ and ectopic progenitors are present in the mutant developing cortex, when Eml1 is absent, at early stages of development (1). Thus, Eml1 is likely to play a role in neural progenitors during cortical development. We performed cell and molecular biology assays aiming to elucidate the function of Eml1 in neural progenitors, and explored the VZ of the HeCo mutant in order to find morphological perturbations that might explain the initiation of SBH formation (3). As part of this study, we searched for Eml1 molecular partners by pull-downs from mouse cortical extracts at embryonic day E13.5 and mass spectrometry (MS) analyses in order to identify the molecular pathways in which the protein is involved (3). Eml1 is formed by an N-terminal region that contains a dimerization domain and a C-terminal region that forms a ‘tandem atypical propeller in EMLs’ (TAPE) domain. The isolated N-terminal domain strongly binds MTs, while the C-terminal domain preferentially binds tubulin, and its beta-propeller structure is thought also to mediate the interaction with other molecules (4,5). We focused for this study on the N-terminal part of the protein (amino acids 1-178). Future study will validate or elucidate new interactions by using the C-terminal domain and/or the full-length protein. The results obtained from the N terminal MS data, integrated with other experimental findings, allow us to insert Eml1 in a network of proteins that are likely to regulate the assembly and function of the mitotic spindle in neural progenitors (3). More precisely, we showed that the protein regulates MT dynamics and its loss leads to perturbations in metaphase spindle length, which in turn impact progenitor morphology and behavior (3). References 1. Kielar, M., et al. Mutations in Eml1 lead to ectopic progenitors and neuronal heterotopia in mouse and human. Nat. Neurosci. 17, 923–933 (2014). 2. Bizzotto, S., & Francis, F. Morphological and functional aspects of progenitors perturbed in cortical malformations. Front Cell Neurosci. 9, 30; 10.3389/fncel00030 (2015). 3. Bizzotto, S., et al. Eml1 loss impairs apical progenitor spindle length and soma shape in the developing cerebral cortex. 4. Richards, M. W., et al. Crystal structure of EML1 reveals the basis for Hsp90 dependence of oncogenic EML4-ALK by disruption of an atypical β-propeller domain. Proc. Natl. Acad. Sci. U.S.A. 111, 5195–5200 (2014). 5. Richards, M. W., et al. Microtubule association of EML proteins and the EML4-ALK variant 3 oncoprotein require an N-terminal trimerization domain. Biochem. J. 467, 529–536 (2015).
2017-12-19 | PXD006837 | Pride
Project description:The domestic ferret (Mustela putorius furo) has been used as animal model for decades, largely because its susceptibility to infection with a large number of pathogens such as influenza virus, SARS Corona virus and Canine distemper virus. Despite its importance for biomedical research, little is known about the genome of the M. Furo. The number of reagents for molecular and immunological analysis is thus restricted. To circumvent this, we present here a parallel sequencing effort to produce an extensive EST dataset derived from a normalized ferret cDNA library made from mRNA from ferret blood, liver, lung, spleen and brain. We produced more than 500000 sequence reads that were assembled into over 15000 partial ferret transcripts. These ESTs were combined with the available ferret sequences in the GenBank to develop a ferret specific microarray platform. Using this array, we detected tissue specific expression patterns which were confirmed by quantitative real time PCR assays and comparison to orthologous transcription profiles of mouse and human. We also present a set of 41 ferret transcript with even transcription profile across the tested tissues, indicating their usefulness as housekeeping genes. This study paves way for development of additional reagents for analysis of the ferret model.
2010-09-13 | GSE19398 | GEO
Project description:Severe fever with thrombocytopenia syndrome phlebovirus (SFTSV), listed in the WHO most dangerous pathogens, has 12-30% fatality rates with a characteristic thrombocytopenia syndrome. With a majority of clinically diagnosed SFTSV patients older than ~50 years, age is a critical risk factor for SFTSV morbidity and mortality. Here, we report an age-dependent ferret model of SFTSV infection and pathogenesis that fully recapitulates the clinical manifestations of human infections. While young adult ferrets (≤2 years old) did not show any clinical symptoms and mortality, SFTSV-infected aged ferrets (≥4 years old) demonstrated severe thrombocytopenia, reduced white blood cells, and high fever with 93% mortality rate. Moreover, significantly higher viral load was observed in aged ferrets. Transcriptome analysis of SFTSV-infected young ferrets revealed strong interferon-mediated anti-viral signaling, whereas inflammatory immune responses were markedly upregulated and persisted in aged ferrets. Thus, this immunocompetent age-dependent ferret model should be useful for anti-SFTSV therapy and vaccine development.
2018-10-30 | GSE121911 | GEO
Project description:Domestic ferret with Bionano hybrid scaffolds
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