scholarly journals Integrative analysis identifies key molecular signatures underlying neurodevelopmental deficits in fragile X syndrome

2019 ◽  
Author(s):  
Kagistia Hana Utami ◽  
Niels H. Skotte ◽  
Ana R. Colaço ◽  
Nur Amirah Binte Mohammad Yusof ◽  
Bernice Sim ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Neurodevelopmental Disorder ◽  
Embryonic Stem ◽  
Neural Progenitor Cell ◽  
Integrative Analysis ◽  
Network Activity ◽  
Neural Cells ◽  
Molecular Signatures ◽  
Neurodevelopmental Abnormalities

AbstractFragile X syndrome (FXS) is an incurable neurodevelopmental disorder with no effective treatment. FXS is caused by epigenetic silencing ofFMR1and loss of FMRP expression. To investigate the consequences of FMRP deficiency in the context of human physiology, we established isogenicFMR1knockout (FMR1KO) human embryonic stem cells (hESCs). Integrative analysis of the transcriptomic and proteomic profiles of hESC-derived FMRP-deficient neurons revealed several dysregulated pathways important for brain development including processes related to axon development, neurotransmission, and the cell cycle. We functionally validated alterations in a number of these pathways, showing abnormal neural rosette formation and increased neural progenitor cell proliferation inFMR1KO cells. We further demonstrated neurite outgrowth and branching deficits along with impaired electrophysiological network activity in FMRP-deficient neurons. Using isogenicFMR1KO hESC-derived neurons, we reveal key molecular signatures and neurodevelopmental abnormalities arising from loss of FMRP. We anticipate that theFMR1KO hESCs and the neuronal transcriptome and proteome datasets will provide a platform to delineate the pathophysiology of FXS in human neural cells.

scholarly journals Integrative Analysis Identifies Key Molecular Signatures Underlying Neurodevelopmental Deficits in Fragile X Syndrome

2020 ◽  
Vol 88 (6) ◽  
pp. 500-511 ◽  
Author(s):  
Kagistia Hana Utami ◽  
Niels H. Skotte ◽  
Ana R. Colaço ◽  
Nur Amirah Binte Mohammad Yusof ◽  
Bernice Sim ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Integrative Analysis ◽  
Molecular Signatures ◽  
Neurodevelopmental Deficits

scholarly journals Novel fragile X syndrome 2D and 3D brain models based on human isogenic FMRP-KO iPSCs

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Carlo Brighi ◽  
Federico Salaris ◽  
Alessandro Soloperto ◽  
Federica Cordella ◽  
Silvia Ghirga ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Cortical Neurons ◽  
Fragile X ◽  
Neurodevelopmental Disorder ◽  
Functional Characterization ◽  
Model Systems ◽  
Network Activity ◽  
Knock Out ◽  
2D And 3D

AbstractFragile X syndrome (FXS) is a neurodevelopmental disorder, characterized by intellectual disability and sensory deficits, caused by epigenetic silencing of the FMR1 gene and subsequent loss of its protein product, fragile X mental retardation protein (FMRP). Delays in synaptic and neuronal development in the cortex have been reported in FXS mouse models; however, the main goal of translating lab research into pharmacological treatments in clinical trials has been so far largely unsuccessful, leaving FXS a still incurable disease. Here, we generated 2D and 3D in vitro human FXS model systems based on isogenic FMR1 knock-out mutant and wild-type human induced pluripotent stem cell (hiPSC) lines. Phenotypical and functional characterization of cortical neurons derived from FMRP-deficient hiPSCs display altered gene expression and impaired differentiation when compared with the healthy counterpart. FXS cortical cultures show an increased number of GFAP positive cells, likely astrocytes, increased spontaneous network activity, and depolarizing GABAergic transmission. Cortical brain organoid models show an increased number of glial cells, and bigger organoid size. Our findings demonstrate that FMRP is required to correctly support neuronal and glial cell proliferation, and to set the correct excitation/inhibition ratio in human brain development.

scholarly journals Novel fragile X syndrome 2D and 3D brain models based on human isogenic FMRP-KO iPSCs

2020 ◽  
Author(s):  
Carlo Brighi ◽  
Federico Salaris ◽  
Alessandro Soloperto ◽  
Federica Cordella ◽  
Silvia Ghirga ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Cortical Neurons ◽  
Fragile X ◽  
Neurodevelopmental Disorder ◽  
Functional Characterization ◽  
Model Systems ◽  
Network Activity ◽  
Knock Out ◽  
2D And 3D

ABSTRACTFragile X syndrome (FXS) is a neurodevelopmental disorder, characterized by intellectual disability and sensory deficits, caused by epigenetic silencing of the FMR1 gene and subsequent loss of its protein product, fragile X mental retardation protein (FMRP). Delays in synaptic and neuronal development in the cortex have been reported in FXS mouse models, however, the main goal of translating lab research into pharmacological treatments in clinical trials has been so far largely unsuccessful, leaving FXS a still incurable disease. Here, we generated 2D and 3D in vitro human FXS model systems based on isogenic FMR1 knock-out mutant and wild-type human induced pluripotent stem cell (hiPSC) lines. Phenotypical and functional characterization of cortical neurons derived from FMRP-deficient hiPSCs display altered gene expression and impaired differentiation when compared with the healthy counterpart. FXS cortical cultures show increased proliferation of GFAP positive cells, likely astrocytes, increased spontaneous network activity and depolarizing GABAergic transmission. Cortical brain organoid models show increased proliferation of glial cells, and bigger organoid size. Our findings demonstrate that FMRP is required to correctly support neuronal and glial cell proliferation, and to set the correct excitation/inhibition ratio in human brain development.

scholarly journals Impaired inhibitory control of cortical synchronization in fragile X syndrome

2011 ◽  
Vol 106 (5) ◽  
pp. 2264-2272 ◽  
Author(s):  
Scott M. Paluszkiewicz ◽  
Jose Luis Olmos-Serrano ◽  
Joshua G. Corbin ◽  
Molly M. Huntsman
Keyword(s):  
Fragile X Syndrome ◽  
Pyramidal Neurons ◽  
Metabotropic Glutamate Receptor ◽  
Fragile X ◽  
Neurodevelopmental Disorder ◽  
Synaptic Inhibition ◽  
Cortical Interneuron ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Functional Defect

Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by severe cognitive impairments, sensory hypersensitivity, and comorbidities with autism and epilepsy. Fmr1 knockout (KO) mouse models of FXS exhibit alterations in excitatory and inhibitory neurotransmission, but it is largely unknown how aberrant function of specific neuronal subtypes contributes to these deficits. In this study we show specific inhibitory circuit dysfunction in layer II/III of somatosensory cortex of Fmr1 KO mice. We demonstrate reduced activation of somatostatin-expressing low-threshold-spiking (LTS) interneurons in response to the group I metabotropic glutamate receptor (mGluR) agonist 3,5-dihydroxyphenylglycine (DHPG) in Fmr1 KO mice, resulting in impaired synaptic inhibition. Paired recordings from pyramidal neurons revealed reductions in synchronized synaptic inhibition and coordinated spike synchrony in response to DHPG, indicating a weakened LTS interneuron network in Fmr1 KO mice. Together, these findings reveal a functional defect in a single subtype of cortical interneuron in Fmr1 KO mice. This defect is linked to altered activity of the cortical network in line with the FXS phenotype.

scholarly journals Developmental Study of Fragile X Syndrome Using Human Embryonic Stem Cells Derived from Preimplantation Genetically Diagnosed Embryos

2007 ◽  
Vol 1 (5) ◽  
pp. 568-577 ◽  
Author(s):  
Rachel Eiges ◽  
Achia Urbach ◽  
Mira Malcov ◽  
Tsvia Frumkin ◽  
Tamar Schwartz ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Fragile X Syndrome ◽  
Human Embryonic Stem Cells ◽  
Fragile X ◽  
Embryonic Stem ◽  
Developmental Study

scholarly journals Targeted Reactivation of FMR1 Transcription in Fragile X Syndrome Embryonic Stem Cells

2018 ◽  
Author(s):  
Jill M. Haenfler ◽  
Geena Skariah ◽  
Caitlin M. Rodriguez ◽  
Andre Monteiro da Rocha ◽  
Jack M. Parent ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Embryonic Stem ◽  
Transcriptional Silencing ◽  
Hesc Line ◽  
Human Patient ◽  
Cgg Repeat ◽  
Heterochromatin Formation ◽  
Fmr1 Mrna

ABSTRACTFragile X Syndrome (FXS) is the most common inherited cause of intellectual disability and autism. It results from expansion of a CGG nucleotide repeat in the 5’ untranslated region of FMR1. Large expansions elicit repeat and promoter hyper-methylation, heterochromatin formation, FMR1 transcriptional silencing, and loss of the Fragile X protein, FMRP. Efforts aimed at correcting the sequelae resultant from FMRP loss have thus far proven insufficient, perhaps because of FMRP’s pleiotropic functions. As the repeats do not disrupt the FMRP coding sequence, reactivation of endogenous FMR1 gene expression could correct the proximal event in FXS pathogenesis. Here we utilize the CRISPR/dCAS9 system to selectively re-activate transcription from the silenced FMR1 locus. Fusion of the transcriptional activator VP192 to dCAS9 robustly enhances FMR1 transcription and increases FMRP levels when targeted directly to the CGG repeat in human cells. Using a previously uncharacterized FXS human embryonic stem cell (hESC) line which acquires transcriptional silencing with serial passaging, we achieved locus-specific transcriptional re-activation of FMR1 mRNA expression despite promoter and repeat methylation. These studies demonstrate that FMR1 mRNA expression can be selectively reactivated in human patient cells, creating a pathway forward for therapeutic development in Fragile X Syndrome.

scholarly journals Consumption of Breast Milk Is Associated with Decreased Prevalence of Autism in Fragile X Syndrome

Nutrients ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1785
Author(s):  
Cara J. Westmark
Keyword(s):  
Breast Milk ◽  
Fragile X Syndrome ◽  
Study Design ◽  
Early Life ◽  
Fragile X ◽  
Neurodevelopmental Disorder ◽  
Research Database ◽  
Retrospective Survey ◽  
Fold Reduction

Breastfeeding is associated with numerous health benefits, but early life nutrition has not been specifically studied in the neurodevelopmental disorder fragile X syndrome (FXS). Herein, I evaluate associations between the consumption of breast milk during infancy and the prevalence of autism, allergies, diabetes, gastrointestinal (GI) problems and seizures in FXS. The study design was a retrospective survey of families enrolled in the Fragile X Online Registry and Accessible Research Database (FORWARD). There was a 1.7-fold reduction in the prevalence of autism in FXS participants who were fed breast milk for 12 months or longer. There were strong negative correlations between increased time the infant was fed breast milk and the prevalence of autism and seizures and moderate negative correlations with the prevalence of GI problems and allergies. However, participants reporting GI problems or allergies commenced these comorbidities significantly earlier than those not fed breast milk. Parsing the data by sex indicated that males exclusively fed breast milk exhibited decreased prevalence of GI problems and allergies. These data suggest that long-term or exclusive use of breast milk is associated with reduced prevalence of key comorbidities in FXS, although breast milk is associated with the earlier development of GI problems and allergies.

scholarly journals An “Omic” Overview of Fragile X Syndrome

Biology ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 433
Author(s):  
Olivier Dionne ◽  
François Corbin
Keyword(s):  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Fragile X ◽  
Neurodevelopmental Disorder ◽  
Medical Problems ◽  
Biochemical Alterations ◽  
Fragile X Mental Retardation ◽  
Wide Range

Fragile X syndrome (FXS) is a neurodevelopmental disorder associated with a wide range of cognitive, behavioral and medical problems. It arises from the silencing of the fragile X mental retardation 1 (FMR1) gene and, consequently, in the absence of its encoded protein, FMRP (fragile X mental retardation protein). FMRP is a ubiquitously expressed and multifunctional RNA-binding protein, primarily considered as a translational regulator. Pre-clinical studies of the past two decades have therefore focused on this function to relate FMRP’s absence to the molecular mechanisms underlying FXS physiopathology. Based on these data, successful pharmacological strategies were developed to rescue fragile X phenotype in animal models. Unfortunately, these results did not translate into humans as clinical trials using same therapeutic approaches did not reach the expected outcomes. These failures highlight the need to put into perspective the different functions of FMRP in order to get a more comprehensive understanding of FXS pathophysiology. This work presents a review of FMRP’s involvement on noteworthy molecular mechanisms that may ultimately contribute to various biochemical alterations composing the fragile X phenotype.

scholarly journals The Contribution of Pluripotent Stem Cell (PSC)-Based Models to the Study of Fragile X Syndrome (FXS)

2019 ◽  
Vol 9 (2) ◽  
pp. 42 ◽  
Author(s):  
Manar Abu Diab ◽  
Rachel Eiges
Keyword(s):  
Stem Cells ◽  
Gene Silencing ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Embryonic Stem ◽  
Cgg Repeat ◽  
Molecular Features ◽  
Epigenetic Gene Silencing ◽  
Mental Retardation Protein ◽  
Induced Pluripotent

Fragile X syndrome (FXS) is the most common heritable form of cognitive impairment. It results from a deficiency in the fragile X mental retardation protein (FMRP) due to a CGG repeat expansion in the 5′-UTR of the X-linked FMR1 gene. When CGGs expand beyond 200 copies, they lead to epigenetic gene silencing of the gene. In addition, the greater the allele size, the more likely it will become unstable and exhibit mosaicism for expansion size between and within tissues in affected individuals. The timing and mechanisms of FMR1 epigenetic gene silencing and repeat instability are far from being understood given the lack of appropriate cellular and animal models that can fully recapitulate the molecular features characteristic of the disease pathogenesis in humans. This review summarizes the data collected to date from mutant human embryonic stem cells, induced pluripotent stem cells, and hybrid fusions, and discusses their contribution to the investigation of FXS, their key limitations, and future prospects.

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