Role of phosphodiesterases in the pathophysiology of neurodevelopmental disorders

Delhaye, Sébastien; Bardoni, Barbara

doi:10.1038/s41380-020-00997-9

Cited by 67 publications

(53 citation statements)

References 149 publications

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“…In this study, we demonstrated that a receptor and a core transcription factor of Wnt signaling were both targets of miR-139 regulating GSC self-renewal and differentiation. On the other hand, PDE2A belongs to the phosphodiesterase (PDE) family, which is responsible for the hydrolysis of cyclic phosphate to balance the concentration of cAMP and cGMP [27,38]. The cyclic nucleotides cAMP and cGMP are ubiquitous second messengers that modulate a wide array of intracellular processes [39,40].…”

Section: Discussionmentioning

confidence: 99%

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miR-139/PDE2A-Notch1 feedback circuit represses stemness of gliomas by inhibiting Wnt/β-catenin signaling

Ren

Zhao

et al. 2021

Int. J. Biol. Sci.

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Rationale:The malignant phenotypes of glioblastomas (GBMs) are primarily attributed to glioma stem cells (GSCs). Our previous study and other reports have suggested that both miR-139 and its host gene PDE2A are putative antitumor genes in various cancers. The aim of this study was to investigate the roles and mechanisms of miR-139/PDE2A in GSC modulation. Methods: Clinical samples were used to determine miR-139/PDE2A expression. Patient-derived glioma stem-like cells (PD-GSCs) were stimulated for immunofluorescent staining, sphere formation assays and orthotopic GBM xenograft models. Bioinformatic analysis and further in vitro experiments demonstrated the downstream molecular mechanisms of miR-139 and PDE2A. OX26/CTX-conjugated PEGylated liposome (OCP) was constructed to deliver miR-139 or PDE2A into glioma tissue specifically. Results: We demonstrated that miR-139 was concomitantly transcribed with its host gene PDE2A. Both PDE2A and miR-139 indicated better prognosis of gliomas and were inversely correlated with GSC stemness. PDE2A or miR-139 overexpression suppressed the stemness of PD-GSCs. FZD3 and β-catenin, which induced Wnt/β-catenin signaling activation, were identified as targets of miR-139 and mediated the effects of miR-139 on GSCs. Meanwhile, PDE2A suppressed Wnt/β-catenin signaling by inhibiting cAMP accumulation and GSK-3β phosphorylation, thereby modulating the self-renewal of PD-GSCs. Notably, Notch1, which is also a target of miR-139, suppressed PDE2A/miR-139 expression directly via downstream Hes1, indicating that miR-139 promoted its own expression by the miR-139-Notch1/Hes1 feedback circuit. Expectedly, targeted overexpression miR-139 or PDE2A in glioma with OCP system significantly repressed the stemness and decelerated glioma progression. Conclusions: Our findings elaborate on the inhibitory functions of PDE2A and miR-139 on GSC stemness and tumorigenesis, which may provide new prognostic markers and therapeutic targets for GBMs.

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Section: Discussionmentioning

confidence: 99%

“…The cyclic nucleotides cAMP and cGMP are ubiquitous second messengers that modulate a wide array of intracellular processes [39,40]. The expression of PDEs is tissue specific, and PDE2A is abundant in the brain [38,41]. The aberrant expression of PDE2A causes CNS disorders, such as learning and memory dysfunction [42,43].…”

Section: Discussionmentioning

confidence: 99%

miR-139/PDE2A-Notch1 feedback circuit represses stemness of gliomas by inhibiting Wnt/β-catenin signaling

Ren

Zhao

et al. 2021

Int. J. Biol. Sci.

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“…Targeting cAMP-PKA may thus have the potential to correct both short-and long-term habituation deficits. Promoting cAMP-PKA activity by pharmacological inhibition of phosphodiesterases (PDEs -negative regulators of cAMP), has shown promising results in correcting cognitive impairment in animal models of neurodevelopmental and neurodegenerative disorders, as well as in patients [216]). PDE3 and PDE4 inhibitors have been shown to improve habituation in wild-type and NF1-deficient zebrafish models, respectively.…”

Section: Reference In Legend [179]mentioning

confidence: 99%

Genetics, Molecular Control and Clinical Relevance of Habituation Learning

Blok¹,

Boon²,

Reijmersdal³

et al. 2022

Preprint

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Habituation, the most ancient and fundamental form of learning, manifests already before birth. Neuroscientists have been fascinated for decades by its function as a firewall protecting our brains from sensory information overload and its indispensability for higher cognitive processing. Evidence that habituation learning is affected in autism and related monogenic neurodevelopmental syndromes and their animal models has exponentially grown, but the potential of this convergence to advance both fields is still largely unexploited.In this review, we provide a systematic overview of the genes that to date have been demonstrated to underlie habituation across species. We describe the biological processes they converge on, and highlight core regulatory pathways and repurposable drugs that may alleviate the habituation deficits associated with their dysregulation. We also summarize currently used habituation paradigms and extract the most important arguments from literature that support the crucial role of habituation for cognition in health and disease. We conclude that habituation is a powerful tool to overcome current bottlenecks in research, diagnostics and treatment of neurodevelopmental disorders.

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“…This molecule has been found to be decreased in Mecp2 KO mice and rectifying CREB levels can correct some of the RTT symptoms (Bu et al, 2017). The Fmr1 gene is thought to be bound and therefore regulated by CREB (Kanellopoulos et al, 2012;Rani and Prasad, 2015), however the relationship of CREB signaling to FXS synaptic plasticity requires further investigation, especially considering the role that FMRP has in the modulation of cAMP and cGMP levels, two molecules upstream the CREB expression (Delhaye and Bardoni, 2021). It was shown that In the hippocampus, Cilostazol (an inhibitor of Phosphodiesterase 3) increases the levels of c-fos and of insulin-like growth factor 1 (IGF-1) (Zhao et al, 2010) and activates CREB in PC12 cells (Zheng and Quirion, 2006).…”

Section: Cyclic Adenosine Monophosphate Response Element Binding Proteinmentioning

confidence: 99%

Rett Syndrome and Fragile X Syndrome: Different Etiology With Common Molecular Dysfunctions

Bach

Shovlin

Moriarty

et al. 2021

Front. Cell. Neurosci.

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Rett syndrome (RTT) and Fragile X syndrome (FXS) are two monogenetic neurodevelopmental disorders with complex clinical presentations. RTT is caused by mutations in the Methyl-CpG binding protein 2 gene (MECP2) altering the function of its protein product MeCP2. MeCP2 modulates gene expression by binding methylated CpG dinucleotides, and by interacting with transcription factors. FXS is caused by the silencing of the FMR1 gene encoding the Fragile X Mental Retardation Protein (FMRP), a RNA binding protein involved in multiple steps of RNA metabolism, and modulating the translation of thousands of proteins including a large set of synaptic proteins. Despite differences in genetic etiology, there are overlapping features in RTT and FXS, possibly due to interactions between MeCP2 and FMRP, and to the regulation of pathways resulting in dysregulation of common molecular signaling. Furthermore, basic physiological mechanisms are regulated by these proteins and might concur to the pathophysiology of both syndromes. Considering that RTT and FXS are disorders affecting brain development, and that most of the common targets of MeCP2 and FMRP are involved in brain activity, we discuss the mechanisms of synaptic function and plasticity altered in RTT and FXS, and we consider the similarities and the differences between these two disorders.

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Role of phosphodiesterases in the pathophysiology of neurodevelopmental disorders

Cited by 67 publications

References 149 publications

miR-139/PDE2A-Notch1 feedback circuit represses stemness of gliomas by inhibiting Wnt/β-catenin signaling

miR-139/PDE2A-Notch1 feedback circuit represses stemness of gliomas by inhibiting Wnt/β-catenin signaling

Genetics, Molecular Control and Clinical Relevance of Habituation Learning

Rett Syndrome and Fragile X Syndrome: Different Etiology With Common Molecular Dysfunctions

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