A DNAzyme based knockdown model for Fragile-X syndrome in zebrafish reveals a critical window for therapeutic intervention

Medishetti, Raghavender; Rani, Rita; Kavati, Srinivas; Mahilkar, Anjali; Venkateswarlu, A.; Uday, Suma; Kulkarni, Pushkar; Sevilimedu, Aarti

doi:10.1016/j.vascn.2019.106656

Cited by 14 publications

(28 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However the two studies are inconsistent with respect to fmr1 impact on anxiety where one study reports fmr1 mutants to have anxiolytic behavior (Ng et al, 2013), while the other reports increased anxiety like behavior (Wu et al, 2017). Recently, a zebrafish FMRP knockdown model was created using a DNAzyme based method (Silverman, 2016;Medishetti et al, 2020). Fmr1-specific DNAzymes were electroporated into embryos between the 0 and 4 cell stage to enzymatically cleave complementary fmr1 RNA in order to transiently knockdown FMRP levels (Medishetti et al, 2020).…”

Section: Fmr1mentioning

confidence: 99%

“…Recently, a zebrafish FMRP knockdown model was created using a DNAzyme based method (Silverman, 2016;Medishetti et al, 2020). Fmr1-specific DNAzymes were electroporated into embryos between the 0 and 4 cell stage to enzymatically cleave complementary fmr1 RNA in order to transiently knockdown FMRP levels (Medishetti et al, 2020). DNAzyme treatment successfully reduced fmr1 mRNA and FMR1 protein levels for over 2 days.…”

Section: Fmr1mentioning

confidence: 99%

“…Behavior was observed using an untreated negative control group and a group treated with valproic acid as a positive control as valproic acid is another known model of neurodevelopmental injury and ASD-associated phenotypes (Dwivedi et al, 2019). FMRP knockdown embryos showed increased anxiety, irritability and cognitive impairments at 7 dpf, leading researchers to conclude that DNAzyme based knockdown of FMRP in zebrafish is a valid model of FXS (Medishetti et al, 2020). Summary: FMR1 mutations in humans leads to alterations in synaptic plasticity and dendritic spines.…”

Section: Fmr1mentioning

confidence: 99%

See 2 more Smart Citations

Using Zebrafish to Model Autism Spectrum Disorder: A Comparison of ASD Risk Genes Between Zebrafish and Their Mammalian Counterparts

Rea

Raay

2020

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Autism spectrum disorders (ASDs) are a highly variable and complex set of neurological disorders that alter neurodevelopment and cognitive function, which usually presents with social and learning impairments accompanied with other comorbid symptoms like hypersensitivity or hyposensitivity, or repetitive behaviors. Autism can be caused by genetic and/or environmental factors and unraveling the etiology of ASD has proven challenging, especially given that different genetic mutations can cause both similar and different phenotypes that all fall within the autism spectrum. Furthermore, the list of ASD risk genes is ever increasing making it difficult to synthesize a common theme. The use of rodent models to enhance ASD research is invaluable and is beginning to unravel the underlying molecular mechanisms of this disease. Recently, zebrafish have been recognized as a useful model of neurodevelopmental disorders with regards to genetics, pharmacology and behavior and one of the main foundations supporting autism research (SFARI) recently identified 12 ASD risk genes with validated zebrafish mutant models. Here, we describe what is known about those 12 ASD risk genes in human, mice and zebrafish to better facilitate this research. We also describe several non-genetic models including pharmacological and gnotobiotic models that are used in zebrafish to study ASD.

show abstract

Section: Fmr1mentioning

confidence: 99%

Section: Fmr1mentioning

confidence: 99%

Section: Fmr1mentioning

confidence: 99%

See 1 more Smart Citation

Using Zebrafish to Model Autism Spectrum Disorder: A Comparison of ASD Risk Genes Between Zebrafish and Their Mammalian Counterparts

Rea

Raay

2020

Front. Mol. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Early treatment of the fmr1 knock-down embryos with mavoglurant, an mGluR5 antagonist, reduced anxiety, increased cognition and reduced circling at 7dpf. Treatment with KU046 (an anxiolytic) in the 0-3dpf window also reduced anxiety and repetitive behavior at two doses [ 102 ].…”

Section: Resultsmentioning

confidence: 99%

“…These models revealed important functions of Fmrp, reproduced most of the clinical phenotypes and in consequence would be useful for high-throughput screening of different compounds. As was seen in [ 102 ], early pharmacological treatment would improve the effectiveness of the drugs that could be tested and maybe reduced disease progression. However, the creation of zebrafish models with CGG repeats would allow understanding the function of expansion repeats in X-fragile syndrome and FXTAS.…”

Section: Resultsmentioning

confidence: 99%

Zebrafish Models of Autosomal Dominant Ataxias

Quelle-Regaldie

Sobrido‐Cameán

Barreiro‐Iglesias

et al. 2021

Cells

View full text Add to dashboard Cite

Hereditary dominant ataxias are a heterogeneous group of neurodegenerative conditions causing cerebellar dysfunction and characterized by progressive motor incoordination. Despite many efforts put into the study of these diseases, there are no effective treatments yet. Zebrafish models are widely used to characterize neuronal disorders due to its conserved vertebrate genetics that easily support genetic edition and their optic transparency that allows observing the intact CNS and its connections. In addition, its small size and external fertilization help to develop high throughput assays of candidate drugs. Here, we discuss the contributions of zebrafish models to the study of dominant ataxias defining phenotypes, genetic function, behavior and possible treatments. In addition, we review the zebrafish models created for X-linked repeat expansion diseases X-fragile/fragile-X tremor ataxia. Most of the models reviewed here presented neuronal damage and locomotor deficits. However, there is a generalized lack of zebrafish adult heterozygous models and there are no knock-in zebrafish models available for these diseases. The models created for dominant ataxias helped to elucidate gene function and mechanisms that cause neuronal damage. In the future, the application of new genetic edition techniques would help to develop more accurate zebrafish models of dominant ataxias.

show abstract

Early 7,8-Dihydroxyflavone Administration Ameliorates Synaptic and Behavioral Deficits in the Young FXS Animal Model by Acting on BDNF-TrkB Pathway

et al. 2023

View full text Add to dashboard Cite

Fragile X syndrome (FXS) is the leading inherited form of intellectual disability and the most common known cause of autism spectrum disorders. FXS patients exhibit severe syndromic features and behavioral alterations, including anxiety, hyperactivity, impulsivity, and aggression, in addition to cognitive impairment and seizures. At present, there are no effective treatments or cures for FXS. Previously, we have found the divergence of BDNF-TrkB signaling trajectories is associated with spine defects in early postnatal developmental stages of Fmr1 KO mice. Here, young fragile X mice were intraperitoneal injection of 7,8-Dihydroxy avone (7,8-DHF), which is a high a nity tropomyosin receptor kinase B (TrkB) agonist. 7,8-DHF ameliorated morphological abnormities in dendritic spine and synaptic structure, and rescued synaptic and hippocampus-dependent cognitive dysfunction in young FXS mice. These observed improvement of 7,8-DHF involved decreased protein levels of BDNF, p-TrkB Y816 , p-PLCγ, and p-CaMKII in the hippocampus. In addition, 7,8-DHF intervention in primary hippocampal neurons increased p-TrkB Y816 through activating the PLCγ1-CaMKII signaling pathway leading to improvement of neuronal morphology.This study is the rst to account for early life synaptic impairments, neuronal morphological and cognitive delays in FXS in response to the abnormal BDNF-TrkB pathway. Present studies provide novel evidences about the effective early intervention in FXS mice at developmental stages as a strategy to produce powerful impacts on neural development, synaptic plasticity and behaviors.

show abstract

A DNAzyme based knockdown model for Fragile-X syndrome in zebrafish reveals a critical window for therapeutic intervention

Cited by 14 publications

References 45 publications

Using Zebrafish to Model Autism Spectrum Disorder: A Comparison of ASD Risk Genes Between Zebrafish and Their Mammalian Counterparts

Using Zebrafish to Model Autism Spectrum Disorder: A Comparison of ASD Risk Genes Between Zebrafish and Their Mammalian Counterparts

Zebrafish Models of Autosomal Dominant Ataxias

Early 7,8-Dihydroxyflavone Administration Ameliorates Synaptic and Behavioral Deficits in the Young FXS Animal Model by Acting on BDNF-TrkB Pathway

Contact Info

Product

Resources

About