Dataset Information

Zebrafish models of cerebrovascular disease.

ABSTRACT: Perturbations in cerebral blood flow and abnormalities in blood vessel structure are the hallmarks of cerebrovascular disease. While there are many genetic and environmental factors that affect these entities through a heterogeneous group of disease processes, the ultimate final pathologic insult in humans is defined as a stroke, or damage to brain parenchyma. In the case of ischemic stroke, blood fails to reach its target destination whereas in hemorrhagic stroke, extravasation of blood occurs outside of the blood vessel lumen, resulting in direct damage to brain parenchyma. As these acute events can be neurologically devastating, if not fatal, development of novel therapeutics are urgently needed. The zebrafish (Danio rerio) is an attractive model for the study of cerebrovascular disease because of its morphological and physiological similarity to human cerebral vasculature, its ability to be genetically manipulated, and its fecundity allowing for large-scale, phenotype-based screens.

SUBMITTER: Walcott BP

PROVIDER: S-EPMC3982096 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Zebrafish models of cerebrovascular disease.

Walcott Brian P BP Peterson Randall T RT

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20140212 4

Perturbations in cerebral blood flow and abnormalities in blood vessel structure are the hallmarks of cerebrovascular disease. While there are many genetic and environmental factors that affect these entities through a heterogeneous group of disease processes, the ultimate final pathologic insult in humans is defined as a stroke, or damage to brain parenchyma. In the case of ischemic stroke, blood fails to reach its target destination whereas in hemorrhagic stroke, extravasation of blood occurs ...[more]

PMID: 24517974

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Project description:Startle disease is an inherited neurological disorder that causes affected individuals to suffer noise- or touch-induced non-epileptic seizures, excessive muscle stiffness and neonatal apnea episodes. Mutations known to cause startle disease have been identified in glycine receptor subunit (GLRA1 and GLRB) and glycine transporter (SLC6A5) genes, which serve essential functions at glycinergic synapses. Despite the significant successes in identifying startle disease mutations, many idiopathic cases remain unresolved. Exome sequencing in these individuals will identify new candidate genes. To validate these candidate disease genes, zebrafish is an ideal choice due to rapid knockdown strategies, accessible embryonic stages, and stereotyped behaviors. The only existing zebrafish model of startle disease, bandoneon (beo), harbors point mutations in glrbb (one of two zebrafish orthologs of human GLRB) that cause compromised glycinergic transmission and touch-induced bilateral muscle contractions. In order to further develop zebrafish as a model for startle disease, we sought to identify common phenotypic outcomes of knocking down zebrafish orthologs of two known startle disease genes, GLRA1 and GLRB, using splice site-targeted morpholinos. Although both morphants were expected to result in phenotypes similar to the zebrafish beo mutant, our direct comparison demonstrated that while both glra1 and glrbb morphants exhibited embryonic spasticity, only glrbb morphants exhibited bilateral contractions characteristic of beo mutants. Likewise, zebrafish over-expressing a dominant startle disease mutation (GlyR ?1(R271Q)) exhibited spasticity but not bilateral contractions. Since GlyR ?b can interact with GlyR ? subunits 2-4 in addition to GlyR ?1, loss of the GlyR ?b subunit may produce more severe phenotypes by affecting multiple GlyR subtypes. Indeed, immunohistochemistry of glra1 morphants suggests that in zebrafish, alternate GlyR ? subunits can compensate for the loss of the GlyR ?1 subunit. To address the potential for interplay among GlyR subunits during development, we quantified the expression time-course for genes known to be critical to glycinergic synapse function. We found that GlyR ?2, ?3 and ?4a are expressed in the correct temporal pattern and could compensate for the loss of the GlyR ?1 subunit. Based on our findings, future studies that aim to model candidate startle disease genes in zebrafish should include measures of spasticity and synaptic development.

Project description:The Zebrafish Model Organism Database (ZFIN; https://zfin.org) is the central resource for genetic, genomic, and phenotypic data for zebrafish (Danio rerio) research. ZFIN continuously assesses trends in zebrafish research, adding new data types and providing data repositories and tools that members of the research community can use to navigate data. The many research advantages and flexibility of manipulation of zebrafish have made them an increasingly attractive animal to model and study human disease.To facilitate disease-related research, ZFIN developed support to provide human disease information as well as annotation of zebrafish models of human disease. Human disease term pages at ZFIN provide information about disease names, synonyms, and references to other databases as well as a list of publications reporting studies of human diseases in which zebrafish were used. Zebrafish orthologs of human genes that are implicated in human disease etiology are routinely studied to provide an understanding of the molecular basis of disease. Therefore, a list of human genes involved in the disease with their corresponding zebrafish ortholog is displayed on the disease page, with links to additional information regarding the genes and existing mutations. Studying human disease often requires the use of models that recapitulate some or all of the pathologies observed in human diseases. Access to information regarding existing and published models can be critical, because they provide a tractable way to gain insight into the phenotypic outcomes of the disease. ZFIN annotates zebrafish models of human disease and supports retrieval of these published models by listing zebrafish models on the disease term page as well as by providing search interfaces and data download files to access the data. The improvements ZFIN has made to annotate, display, and search data related to human disease, especially zebrafish models for disease and disease-associated gene information, should be helpful to researchers and clinicians considering the use of zebrafish to study human disease.

Dataset Information

Zebrafish models of cerebrovascular disease.

Publications

Zebrafish models of cerebrovascular disease.

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