Expression pattern of cdkl5 during zebrafish early development: implications for use as model for atypical Rett syndrome

Vitorino, Marta; Cunha, Nídia; Conceição, Natércia; Cancela, M. Leonor

doi:10.1007/s11033-018-4180-1

Cited by 7 publications

(8 citation statements)

References 27 publications

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“…Consistent with previous reports (Katayama et al, 2016;Vitorino et al, 2018), we observed that both the long and short cdkl5 isoforms are expressed in the developing embryo (Fig. 1A&B), suggesting Cdkl5 plays a role in early zebrafish development.…”

Section: Cdkl5 Is Expressed During Early Zebrafish Developmentsupporting

confidence: 93%

Novel preclinical model for CDKL5 deficiency disorder

Serrano

Lee

Douek

et al. 2022

Disease Models &Amp; Mechanisms

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Cyclin-Dependent Kinase-Like-5 (CDKL5) Deficiency Disorder (CDD) is a severe X-linked neurodegenerative disease characterized by early-onset epileptic seizures, low muscle tone, progressive intellectual disability, and severe motor function. CDD affects approximately 1 in 60,000 live births with many patients experiencing a reduced quality of life due to the severity of their neurological symptoms and functional impairment. There are no effective therapies for CDD with current treatments focusing on improving symptoms rather than addressing the underlying causes of the disorder. Zebrafish offer many unique advantages for high-throughput pre-clinical evaluation of potential therapies for neurological diseases, including CDD. In particular, the large number of offspring produced, together with the possibilities for in vivo imaging and genetic manipulation, allows for the detailed assessment of disease pathogenesis and therapeutic discovery. We have characterised a loss of function zebrafish model for CDD, containing a nonsense mutation in cdkl5. cdkl5 mutant zebrafish display defects in neuronal patterning, seizures, microcephaly, and reduced muscle function caused by impaired muscle innervation. This study provides a powerful vertebrate model to investigate CDD disease pathophysiology and allow high-throughput screening for effective therapies.

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Section: Cdkl5 Is Expressed During Early Zebrafish Developmentsupporting

confidence: 93%

Novel preclinical model for CDKL5 deficiency disorder

Serrano

Lee

Douek

et al. 2022

Disease Models &Amp; Mechanisms

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“…Variant 1 is mainly expressed in the brain, while variant 2 is ubiquitously expressed 12 . Although the function and mode of action of Cdkl5 in fish have not been investigated, previous studies conducted in our laboratory showed that cdkl5 expression in zebrafish is in accordance with its known localization in humans 13 . Also, zebrafish cdkl5 structural organization, flanking genomic regions, and putative transcription factor binding sites located in its promoter region appear to be highly conserved when compared to its human ortholog 13 .…”

Section: Introductionmentioning

confidence: 91%

“…Although the function and mode of action of Cdkl5 in fish have not been investigated, previous studies conducted in our laboratory showed that cdkl5 expression in zebrafish is in accordance with its known localization in humans 13 . Also, zebrafish cdkl5 structural organization, flanking genomic regions, and putative transcription factor binding sites located in its promoter region appear to be highly conserved when compared to its human ortholog 13 . The corresponding proteins also show a high degree of sequence conservation, particularly in the catalytic domains required for phosphorylation 13 .…”

Section: Introductionmentioning

confidence: 91%

Cdkl5 mutant zebrafish shows skeletal and neuronal alterations mimicking human CDKL5 deficiency disorder

Varela

Martins

et al. 2022

Sci Rep

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CDKL5 deficiency disorder (CDD) is a rare neurodevelopmental condition characterized primarily by seizures and impairment of cognitive and motor skills. Additional phenotypes include microcephaly, dysmorphic facial features, and scoliosis. Mutations in cyclin-dependent kinase-like 5 (CDKL5) gene, encoding a kinase essential for normal brain development and function, are responsible for CDD. Zebrafish is an accepted biomedical model for the study of several genetic diseases and has many advantages over other models. Therefore, this work aimed to characterize the phenotypic, behavioral, and molecular consequences of the Cdkl5 protein disruption in a cdkl5 mutant zebrafish line (sa21938). cdkl5sa21938 mutants displayed a reduced head size, suggesting microcephaly, a feature frequently observed in CDD individuals. Double staining revealed shorter craniofacial cartilage structures and decrease bone mineralization in cdkl5 homozygous zebrafish indicating an abnormal craniofacial cartilage development and impaired skeletal development. Motor behavior analysis showed that cdkl5sa21938 embryos had less frequency of double coiling suggesting impaired glutamatergic neurotransmission. Locomotor behavior analysis revealed that homozygous embryos swim shorter distances, indicative of impaired motor activity which is one of the main traits of CCD. Although no apparent spontaneous seizures were observed in these models, upon treatment with pentylenetetrazole, seizure behavior and an increase in the distance travelled were observed. Quantitative PCR showed that neuronal markers, including glutamatergic genes were dysregulated in cdkl5sa21938 mutant embryos. In conclusion, homozygous cdkl5sa21938 zebrafish mimic several characteristics of CDD, thus validating them as a suitable animal model to better understand the physiopathology of this disorder.

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“…Two nuclear localization signal sequences and a nuclear export signal are contained in the regulatory domain, which is in the C-terminus. Studies in vitro showed how these signal sequences regulate the intracellular localization of CDKL5 ( 25 , 67 , 68 ). Mutations leading to loss of protein function are thought to be responsible for the neurological alterations that characterize the CDKL5 disorder, but to date little is known about CDKL5 substrates.…”

Section: Rett Syndrome and Rett-related Disordersmentioning

confidence: 99%

Sleep Disorders in Rett Syndrome and Rett-Related Disorders: A Narrative Review

et al. 2022

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Rett Syndrome (RTT) is a rare and severe X-linked developmental brain disorder that occurs primarily in females, with a ratio of 1:10.000. De novo mutations in the Methyl-CpG Binding protein 2 (MECP2) gene on the long arm of X chromosome are responsible for more than 95% cases of classical Rett. In the remaining cases (atypical Rett), other genes are involved such as the cyclin-dependent kinase-like 5 (CDKL5) and the forkhead box G1 (FOXG1). Duplications of the MECP2 locus cause MECP2 duplication syndrome (MDS) which concerns about 1% of male patients with intellectual disability. Sleep disorders are common in individuals with intellectual disability, while the prevalence in children is between 16 and 42%. Over 80% of individuals affected by RTT show sleep problems, with a higher prevalence in the first 7 years of life and some degree of variability in correlation to age and genotype. Abnormalities in circadian rhythm and loss of glutamate homeostasis play a key role in the development of these disorders. Sleep disorders, epilepsy, gastrointestinal problems characterize CDKL5 Deficiency Disorder (CDD). Sleep impairment is an area of overlap between RTT and MECP2 duplication syndrome along with epilepsy, regression and others. Sleep dysfunction and epilepsy are deeply linked. Sleep deprivation could be an aggravating factor of epilepsy and anti-comitial therapy could interfere in sleep structure. Epilepsy prevalence in atypical Rett syndrome with severe clinical phenotype is higher than in classical Rett syndrome. However, RTT present a significant lifetime risk of epilepsy too. Sleep disturbances impact on child's development and patients' families and the evidence for its management is still limited. The aim of this review is to analyze pathophysiology, clinical features, the impact on other comorbidities and the management of sleep disorders in Rett syndrome and Rett-related syndrome.

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Expression pattern of cdkl5 during zebrafish early development: implications for use as model for atypical Rett syndrome

Cited by 7 publications

References 27 publications

Novel preclinical model for CDKL5 deficiency disorder

Novel preclinical model for CDKL5 deficiency disorder

Cdkl5 mutant zebrafish shows skeletal and neuronal alterations mimicking human CDKL5 deficiency disorder

Sleep Disorders in Rett Syndrome and Rett-Related Disorders: A Narrative Review

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