scholarly journals Identification of FMRP target genes expressed in corticogenesis: implication for common phenotypes among neurodevelopmental disorders

2019 ◽  
Author(s):  
Cristine R. Casingal ◽  
Takako Kikkawa ◽  
Hitoshi Inada ◽  
Noriko Osumi
Keyword(s):  
Transcriptional Control ◽  
Target Genes ◽  
Rna Binding ◽  
Fragile X ◽  
Autism Spectrum ◽  
Mrna Targets ◽  
Significant Difference ◽  
Rna Immunoprecipitation ◽  
The Brain

ABSTRACTFragile X mental retardation protein (FMRP) is encoded by FMR1 gene that is responsible for Fragile X Syndrome (FXS) showing intellectual disability and autism spectrum disorder. FMRP is an RNA binding protein highly expressed in the brain. Although several target genes for FMRP have been identified, limited studies have suggested the role of FMRP in corticogenesis. Here we performed RNA immunoprecipitation sequencing against the murine embryonic neocortex, and identified 124 genes as potential FMRP mRNA targets. We found 48 of these genes as overlapped with autism-related genes, which were categorized in four functional groups: “transcriptional regulation”, “regulation of actin cytoskeleton”, “ubiquitin-mediated proteolysis” and “calcium signaling pathway”. Four of these genes showed significant difference in expression in the cortical primordium of Fmr1-KO mice; Huwe1 and Kat6a increased, while Kmt2c and Apc decreased. Although the change in expression of these four genes was relatively small, these subtle changes due to dysregulated transcription could collectively contribute to impaired corticogenesis to cause phenotypes of FXS. Investigating the transcriptional control of FMRP on its mRNA targets may provide new insight to understand neurodevelopmental pathogenesis of FXS.

scholarly journals Identification of FMRP target mRNAs in the developmental brain: FMRP might coordinate Ras/MAPK, Wnt/β-catenin, and mTOR signaling during corticogenesis

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Cristine R. Casingal ◽  
Takako Kikkawa ◽  
Hitoshi Inada ◽  
Yukio Sasaki ◽  
Noriko Osumi
Keyword(s):  
Brain Development ◽  
Rna Binding ◽  
Fragile X ◽  
Autism Spectrum ◽  
Mtor Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Sequencing Analysis ◽  
Embryonic Brain ◽  
Target Mrnas ◽  
Mrna Targets

AbstractCorticogenesis is one of the most critical and complicated processes during embryonic brain development. Any slight impairment in corticogenesis could cause neurodevelopmental disorders such as Fragile X syndrome (FXS), of which symptoms contain intellectual disability (ID) and autism spectrum disorder (ASD). Fragile X mental retardation protein (FMRP), an RNA-binding protein responsible for FXS, shows strong expression in neural stem/precursor cells (NPCs) during corticogenesis, although its function during brain development remains largely unknown. In this study, we attempted to identify the FMRP target mRNAs in the cortical primordium using RNA immunoprecipitation sequencing analysis in the mouse embryonic brain. We identified 865 candidate genes as targets of FMRP involving 126 and 118 genes overlapped with ID and ASD-associated genes, respectively. These overlapped genes were enriched with those related to chromatin/chromosome organization and histone modifications, suggesting the involvement of FMRP in epigenetic regulation. We further identified a common set of 17 FMRP “core” target genes involved in neurogenesis/FXS/ID/ASD, containing factors associated with Ras/mitogen-activated protein kinase, Wnt/β-catenin, and mammalian target of rapamycin (mTOR) pathways. We indeed showed overactivation of mTOR signaling via an increase in mTOR phosphorylation in the Fmr1 knockout (Fmr1 KO) neocortex. Our results provide further insight into the critical roles of FMRP in the developing brain, where dysfunction of FMRP may influence the regulation of its mRNA targets affecting signaling pathways and epigenetic modifications.

scholarly journals Identification of TIA1 mRNA targets during human neuronal development

2021 ◽  
Author(s):  
Loryn P. Byres ◽  
Marat Mufteev ◽  
Kyoko E. Yuki ◽  
Wei Wei ◽  
Alina Piekna ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Neural Progenitor Cells ◽  
Neuronal Development ◽  
Rna Binding ◽  
Embryonic Stem ◽  
Autism Spectrum ◽  
Protein Levels ◽  
Mrna Targets ◽  
Autism Spectrum Disorder Risk ◽  
Rna Immunoprecipitation

Abstract Background Neuronal development is a tightly controlled process involving multi-layered regulatory mechanisms. While transcriptional pathways regulating neurodevelopment are well characterized, post-transcriptional programs are still poorly understood. TIA1 is an RNA-binding protein that can regulate splicing, stability, or translation of target mRNAs, and has been shown to play critical roles in stress response and neurodevelopment. However, the identity of mRNAs regulated by TIA1 during neurodevelopment under unstressed conditions is still unknown. Methods and Results To identify the mRNAs targeted by TIA1 during the first stages of human neurodevelopment, we performed RNA immunoprecipitation-sequencing (RIP-seq) on human embryonic stem cells (hESCs) and derived neural progenitor cells (NPCs), and cortical neurons under unstressed conditions. While there was no change in TIA1 protein levels, the number of TIA1 targeted mRNAs decreased from pluripotent cells to neurons. We identified 2400, 845, and 330 TIA1 mRNA targets in hESCs, NPC, and neurons, respectively. The vast majority of mRNA targets in hESC were genes associated with neurodevelopment and included autism spectrum disorder-risk genes that were not bound in neurons. Additionally, we found that most TIA1 mRNA targets have reduced ribosomal engagement levels. Conclusion Our results reveal TIA1 mRNA targets in hESCs and during human neurodevelopment, indicate that translation repression is a key process targeted by TIA1 binding and implicate TIA1 function in neuronal differentiation.

scholarly journals Identification of FMRP target mRNAs in the developmental brain: FMRP might coordinate Ras/MAPK, Wnt/ß-catenin, and mTOR signaling during corticogenesis

2020 ◽  
Author(s):  
Cristine R. Casingal ◽  
Takako Kikkawa ◽  
Hitoshi Inada ◽  
Yukio Sasaki ◽  
Noriko Osumi
Keyword(s):  
Brain Development ◽  
Rna Binding ◽  
Fragile X ◽  
Autism Spectrum ◽  
Mtor Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Sequencing Analysis ◽  
Embryonic Brain ◽  
Target Mrnas ◽  
Mrna Targets

Abstract Corticogenesis is one of the most critical and complicated processes during embryonic brain development. Any slight impairment in corticogenesis could cause neurodevelopmental disorders such as Fragile X syndrome (FXS), of which symptoms contain intellectual disability (ID) and autism spectrum disorder (ASD). Fragile X mental retardation protein (FMRP), an RNA-binding protein responsible for FXS, shows strong expression in neural stem/precursor cells (NPCs) during corticogenesis, although its function during brain development remains largely unknown. In this study, we attempted to identify the FMRP target mRNAs in the mouse cortical primordium using RNA immunoprecipitation sequencing analysis in the mouse embryonic brain. We identified 865 candidate genes as targets of FMRP involving 126 and 118 genes overlapped with ID and ASD-associated genes, respectively. These overlapped genes were enriched with those related to chromatin/chromosome organization and histone modifications, suggesting the involvement of FMRP in epigenetic regulation. We further identified a common set of 17 "core" genes involved in neurogenesis/FXS/ID/ASD, containing factors associated with Ras/mitogen-activated protein kinase, Wnt/ß-catenin, and mTOR pathways. We indeed showed overactivation of mTOR signaling via an increase in mTOR phosphorylation in the Fmr1 knockout (Fmr1 KO) neocortex. Our results provide further insight into the critical roles of FMRP in the developing brain, where dysfunction of FMRP may influence the regulation of its mRNA targets affecting signaling pathways and epigenetic modifications.

scholarly journals Autism-like syndrome is induced by pharmacological suppression of BET proteins in young mice

2015 ◽  
Vol 212 (11) ◽  
pp. 1771-1781 ◽  
Author(s):  
Josefa M. Sullivan ◽  
Ana Badimon ◽  
Uwe Schaefer ◽  
Pinar Ayata ◽  
James Gray ◽  
...  
Keyword(s):  
Target Genes ◽  
Autism Spectrum ◽  
Epigenetic Mechanism ◽  
The Novel ◽  
Neuronal Gene ◽  
Novel Therapeutic Strategies ◽  
The Brain ◽  
Epigenetic Processes ◽  
Young Mice

Studies investigating the causes of autism spectrum disorder (ASD) point to genetic, as well as epigenetic, mechanisms of the disease. Identification of epigenetic processes that contribute to ASD development and progression is of major importance and may lead to the development of novel therapeutic strategies. Here, we identify the bromodomain and extraterminal domain–containing proteins (BETs) as epigenetic regulators of genes involved in ASD-like behaviors in mice. We found that the pharmacological suppression of BET proteins in the brain of young mice, by the novel, highly specific, brain-permeable inhibitor I-BET858 leads to selective suppression of neuronal gene expression followed by the development of an autism-like syndrome. Many of the I-BET858–affected genes have been linked to ASD in humans, thus suggesting the key role of the BET-controlled gene network in the disorder. Our studies suggest that environmental factors controlling BET proteins or their target genes may contribute to the epigenetic mechanism of ASD.

scholarly journals Pioglitazone improves deficits of Fmr1-KO mouse model of Fragile X syndrome by interfering with excessive diacylglycerol signaling

2020 ◽  
Author(s):  
Andréa Geoffroy ◽  
Karima Habbas ◽  
Boglarka Zambo ◽  
Laetitia Schramm ◽  
Arnaud Duchon ◽  
...  
Keyword(s):  
Mouse Model ◽  
Fragile X Syndrome ◽  
Rna Binding ◽  
Fragile X ◽  
Loss Of Function ◽  
Behavioral Alterations ◽  
Specific Proteins ◽  
The Brain

AbstractFragile X syndrome (FXS), the leading cause of familial intellectual disability, is an uncured disease caused by the absence or loss of function of the FMRP protein. FMRP is an RNA binding protein that controls the translation of specific proteins in neurons. A main target of FMRP in neurons is diacylglycerol kinase kappa (DGKk) and the loss of FMRP leads to a loss of DGK activity causing a diacylglycerol excess in the brain. Excessive diacylglycerol signaling could be a significant contributor to the pathomechanism of FXS. Here we tested the contribution of DAG-signaling in Fmr1-KO mouse model of FXS and we show that pioglitazone, a widely prescribed drug for type 2 diabetes, has ability to correct excessive DAG signaling in the brain and rescue behavioral alterations of the Fmr1-KO mouse. This study highlights the role of lipid signaling homeostasis in FXS and provides arguments to support the testing of pioglitazone for treatment of FXS.

scholarly journals Identification of TIA1 mRNA targets during human neuronal development

2021 ◽  
Author(s):  
Loryn P. Byres ◽  
Marat Mufteev ◽  
Kyoko E. Yuki ◽  
Wei Wei ◽  
Alina Piekna ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Neural Progenitor Cells ◽  
Neuronal Development ◽  
Rna Binding ◽  
Embryonic Stem ◽  
Autism Spectrum ◽  
Protein Levels ◽  
Mrna Targets ◽  
Autism Spectrum Disorder Risk ◽  
Rna Immunoprecipitation

AbstractBackgroundNeuronal development is a tightly controlled process involving multi-layered regulatory mechanisms. While transcriptional pathways regulating neurodevelopment are well characterized, post-transcriptional programs are still poorly understood. TIA1 is an RNA-binding protein that can regulate splicing, stability, or translation of target mRNAs, and has been shown to play critical roles in neurodevelopment. However, the identity of mRNAs regulated by TIA1 during neurodevelopment is still unknown.Methods and ResultsTo identify the mRNAs targeted by TIA1 during the first stages of human neurodevelopment, we performed RNA immunoprecipitation-sequencing (RIP-seq) on human embryonic stem cells (hESCs) and derived neural progenitor cells (NPCs), and cortical neurons. While there was no change in TIA1 protein levels, the number of TIA1 targeted mRNAs decreased from pluripotent cells to neurons. We identified 2400, 845, and 330 TIA1 mRNA targets in hESCs, NPC, and neurons, respectively. The vast majority of mRNA targets in hESC were genes associated with neurodevelopment and included autism spectrum disorder-risk genes that were not bound in neurons. Additionally, we found that most TIA1 mRNA targets have reduced ribosomal engagement levels.ConclusionOur results reveal TIA1 mRNA targets in hESCs and during human neurodevelopment, indicate that translation repression is a key process targeted by TIA1 binding and implicate TIA1 function in neuronal differentiation.

Involvement of Phosphodiesterase 2A Activity in the Pathophysiology of Fragile X Syndrome

2018 ◽  
Vol 29 (8) ◽  
pp. 3241-3252 ◽  
Author(s):  
Thomas Maurin ◽  
Francesca Melancia ◽  
Marielle Jarjat ◽  
Liliana Castro ◽  
Lara Costa ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Translational Regulation ◽  
Rna Binding ◽  
Fragile X ◽  
The Social ◽  
Mental Retardation Protein ◽  
Camp And Cgmp ◽  
The Brain

Abstract The fragile X mental retardation protein (FMRP) is an RNA-binding protein involved in translational regulation of mRNAs that play key roles in synaptic morphology and plasticity. The functional absence of FMRP causes the fragile X syndrome (FXS), the most common form of inherited intellectual disability and the most common monogenic cause of autism. No effective treatment is available for FXS. We recently identified the Phosphodiesterase 2A (Pde2a) mRNA as a prominent target of FMRP. PDE2A enzymatic activity is increased in the brain of Fmr1-KO mice, a recognized model of FXS, leading to decreased levels of cAMP and cGMP. Here, we pharmacologically inhibited PDE2A in Fmr1-KO mice and observed a rescue both of the maturity of dendritic spines and of the exaggerated hippocampal mGluR-dependent long-term depression. Remarkably, PDE2A blockade rescued the social and communicative deficits of both mouse and rat Fmr1-KO animals. Importantly, chronic inhibition of PDE2A in newborn Fmr1-KO mice followed by a washout interval, resulted in the rescue of the altered social behavior observed in adolescent mice. Altogether, these results reveal the key role of PDE2A in the physiopathology of FXS and suggest that its pharmacological inhibition represents a novel therapeutic approach for FXS.

scholarly journals FOXP1 syndrome: a review of the literature and practice parameters for medical assessment and monitoring

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Reymundo Lozano ◽  
Catherine Gbekie ◽  
Paige M. Siper ◽  
Shubhika Srivastava ◽  
Jeffrey M. Saland ◽  
...  
Keyword(s):  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Medical Assessment ◽  
Forkhead Box ◽  
Organ Systems ◽  
Practice Parameters ◽  
Assessment And Monitoring ◽  
Multidisciplinary Group ◽  
The Brain

AbstractFOXP1 syndrome is a neurodevelopmental disorder caused by mutations or deletions that disrupt the forkhead box protein 1 (FOXP1) gene, which encodes a transcription factor important for the early development of many organ systems, including the brain. Numerous clinical studies have elucidated the role of FOXP1 in neurodevelopment and have characterized a phenotype. FOXP1 syndrome is associated with intellectual disability, language deficits, autism spectrum disorder, hypotonia, and congenital anomalies, including mild dysmorphic features, and brain, cardiac, and urogenital abnormalities. Here, we present a review of human studies summarizing the clinical features of individuals with FOXP1 syndrome and enlist a multidisciplinary group of clinicians (pediatrics, genetics, psychiatry, neurology, cardiology, endocrinology, nephrology, and psychology) to provide recommendations for the assessment of FOXP1 syndrome.

scholarly journals Study of the role of the transcranial magnetic stimulation on language progress in autism spectrum disorder

2021 ◽  
Vol 37 (1) ◽  
Author(s):  
Mohamed E. Darwish ◽  
Heba W. El-Beshlawy ◽  
Ehab S. Ramadan ◽  
Shimaa M. Serag
Keyword(s):  
Autism Spectrum Disorder ◽  
Transcranial Magnetic Stimulation ◽  
Magnetic Stimulation ◽  
Autism Spectrum ◽  
Language Therapy ◽  
Children With Asd ◽  
Group I ◽  
Mild Improvement ◽  
Significant Difference

Abstract Background Children with autism spectrum disorder (ASD) are almost universally delayed in the acquisition of spoken language as primary means of communication so they tend to have restricted outcomes in terms of independence and integration. Transcranial magnetic stimulation (TMS) is a promising, emerging tool for the study (study and modulate excitability and plasticity, applied in single pulses to investigate corticospinal excitability, pairs of pulses to study intracortical inhibition and facilitation) and potential treatment of ASD. The purpose of this study is to evaluate the role of repetitive TMS in language progress in children with ASD. Results There was a statistically significant clinical improvement in patients receiving active TMS (group I) comparing baseline Childhood Autism Rating Scale (CARS) assessment and after treatment (P ≤ 0.05). There was mild improvement with no significant difference between the patients receiving active TMS (group I) and those of sham TMS (group II), and both groups received language therapy as regard post-treatment CARS. There was significant difference in improvement between the two groups according to eye contact (P ≤ 0.05). There was significant improvement in response to examiner (P ≤ 0.05). There was mild improvement with no statistically significant difference in attention between the two groups. There was significant difference in improvement between the two groups according to active expressive language. There was no statistically significant difference in passive vocabulary between the two groups. Conclusion Repetitive transcranial magnetic stimulation (rTMS) over left inferior frontal gyrus may be a safe and effective way of improving language of ASD. The joint application of rTMS and standard language therapy may lead to more rapid improvement in the language progress of children with ASD.

scholarly journals Star-PAP RNA Binding Landscape Reveals Novel Role of Star-PAP in mRNA Metabolism That Requires RBM10-RNA Association

2021 ◽  
Vol 22 (18) ◽  
pp. 9980
Author(s):  
Ganesh R. Koshre ◽  
Feba Shaji ◽  
Neeraja K. Mohanan ◽  
Nimmy Mohan ◽  
Jamshaid Ali ◽  
...  
Keyword(s):  
Rna Binding ◽  
Coding Region ◽  
High Association ◽  
Target Mrnas ◽  
Mrna Metabolism ◽  
Mrna Targets ◽  
Genome Wide ◽  
Global Profile ◽  
Specific Mrna

Star-PAP is a non-canonical poly(A) polymerase that selects mRNA targets for polyadenylation. Yet, genome-wide direct Star-PAP targets or the mechanism of specific mRNA recognition is still vague. Here, we employ HITS-CLIP to map the cellular Star-PAP binding landscape and the mechanism of global Star-PAP mRNA association. We show a transcriptome-wide association of Star-PAP that is diminished on Star-PAP depletion. Consistent with its role in the 3′-UTR processing, we observed a high association of Star-PAP at the 3′-UTR region. Strikingly, there is an enrichment of Star-PAP at the coding region exons (CDS) in 42% of target mRNAs. We demonstrate that Star-PAP binding de-stabilises these mRNAs indicating a new role of Star-PAP in mRNA metabolism. Comparison with earlier microarray data reveals that while UTR-associated transcripts are down-regulated, CDS-associated mRNAs are largely up-regulated on Star-PAP depletion. Strikingly, the knockdown of a Star-PAP coregulator RBM10 resulted in a global loss of Star-PAP association on target mRNAs. Consistently, RBM10 depletion compromises 3′-end processing of a set of Star-PAP target mRNAs, while regulating stability/turnover of a different set of mRNAs. Our results establish a global profile of Star-PAP mRNA association and a novel role of Star-PAP in the mRNA metabolism that requires RBM10-mRNA association in the cell.

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