FMR1 loss in a human stem cell model reveals early changes to intrinsic membrane excitability.

FMR1 loss in a human stem cell model reveals early changes to intrinsic membrane excitability. Dev Biol. 2020 Sep 22;: Authors: Susco SG, Arias-García MA, López-Huerta VG, Beccard A, Bara AM, Moffitt J, Korn J, Fu Z, Barrett LE Abstract Fragile X mental retardation 1 (FMR1) encodes the RNA binding protein FMRP. Loss of FMRP drives Fragile X syndrome (FXS), the leading inherited cause of intellectual disability and a leading monogenic cause of autism. While cortical hyperexcitability is a hallmark of FXS, the reported phenotypes and underlying mechanisms, including alterations in synaptic transmission and ion channel properties, are heterogeneous and at times contradictory. Here, we report the generation of new isogenic FMR1y/+ and FMR1y/- human pluripotent stem cell (hPSC) lines using CRISPR-Cas9 to facilitate the study of how complete FMRP loss, independent of genetic background, drives molecular and cellular alterations relevant for FXS. After differentiating these stem cell tools into excitatory neurons, we systematically assessed the impact of FMRP loss on intrinsic membrane and synaptic properties over time. Using whole-cell patch clamp analyses, we found that FMR1y/- neurons overall showed an increased intrinsic membrane excitability compared to age-matched FMR1y/+ controls, with no discernable alternations in synaptic transmission. Surprisingly, longitudinal analyses of cell intrinsic defects revealed that a majority of significant c...
Source: Developmental Biology - Category: Biology Authors: Tags: Dev Biol Source Type: research

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FMR1 has a dynamic trinucleotide CGG repeat element in the promotor region, and when the CGG repeat expands to a repeat length above 200 during maternal transmission, FMR1 becomes methylated and its gene and protein expressions are silenced. Deficiency of the FMR1 protein product FMRP causes fragile X syndrome (FXS), the most commonly inherited form of intellectual disability and autism spectrum disorder. FXS is associated with a wide spectrum of comorbidities, including seizures, sensory hypersensitivity, hyperactivity, impulsivity, anxiety, and impaired learning (1).
Source: Biological Psychiatry - Category: Psychiatry Authors: Tags: Early Career Investigator Commentary Source Type: research
RNA-binding proteins (RNA-BPs) play critical roles in development and disease to regulate gene expression. However, genome-wide identification of their targets in primary human cells has been challenging. Here, we applied a modified CLIP-seq strategy to identify genome-wide targets of the FMRP translational regulator 1 (FMR1), a brain-enriched RNA-BP, whose deficiency leads to Fragile X Syndrome (FXS), the most prevalent inherited intellectual disability. We identified FMR1 targets in human dorsal and ventral forebrain neural progenitors and excitatory and inhibitory neurons differentiated from human pluripotent stem cells...
Source: Genome Research - Category: Genetics & Stem Cells Authors: Tags: RESEARCH Source Type: research
Publication date: Available online 28 June 2019Source: Stem Cell ResearchAuthor(s): Subhajit Giri, Meera Purushottam, Biju Viswanath, Ravi S. MuddashettyAbstractMutations in FMR1 gene is the cause of Fragile X Syndrome (FXS) leading inherited cause of intellectual disability and autism spectrum disorders. FMR1 gene encodes Fragile X Mental Retardation Protein (FMRP) which is a RNA binding protein and play important role in synaptic plasticity and translational regulation in neurons. We have generated a homozygous FMR1 knockout (FMR1-KO) hESC line using CRISPR/Cas9 based genome editing. It created a homozygous 280 nucleotid...
Source: Stem Cell Research - Category: Stem Cells Source Type: research
In conclusion, we further advanced the molecular understanding of mitochondrial dysfunction in RTT. Intensified mitochondrial O2 consumption, increased mitochondrial ROS generation and disturbed redox balance in mitochondria and cytosol may represent a causal chain, which provokes dysregulated proteins, oxidative tissue damage, and contributes to neuronal network dysfunction in RTT. Introduction Rett syndrome (RTT) is a progressive neurodevelopmental disorder. It primarily affects females, who show the first obvious symptoms within 6–18 months after birth. Among the characteristics are a regression of mental ...
Source: Frontiers in Physiology - Category: Physiology Source Type: research
Novel Contribution of Secreted Amyloid-β Precursor Protein to White Matter Brain Enlargement in Autism Spectrum Disorder Deborah K. Sokol1, Bryan Maloney2, Cara J. Westmark3 and Debomoy K. Lahiri2,4* 1Pediatrics Section, Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, United States2Indiana Alzheimers Disease Center, Department of Psychiatry, Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, IN, United States3Department of Neurology, University of Wisconsin, Madison, WI, United States4Department of Medical and Molecular Genetics, Indiana Un...
Source: Frontiers in Psychiatry - Category: Psychiatry Source Type: research
Publication date: 8 June 2018 Source:Progress in Neuro-Psychopharmacology and Biological Psychiatry, Volume 84, Part B Author(s): Katrin Linda, Carol Fiuza, Nael Nadif Kasri A major challenge in clinical genetics and medicine is represented by genetically and phenotypically highly diverse neurodevelopmental disorders, like for example intellectual disability and autism. Intellectual disability is characterized by substantial limitations in cognitive function and adaptive behaviour. At the cellular level, this is reflected by deficits in synaptic structure and plasticity and therefore has been coined as a synaptic disorder...
Source: Progress in Neuro Psychopharmacology and Biological Psychiatry - Category: Psychiatry Source Type: research
Scientists have caught the first glimpse of molecules shuttling along a sort of highway running the length of neural stem cells, which are crucial to the development of new neurons. This new view has given them an intriguing clue that a protein deficient in Fragile X syndrome, an autism-related disorder that causes intellectual disability, is responsible for moving at least some of this molecular cargo up and down the stem cells.
Source: ScienceDaily Headlines - Category: Science Source Type: news
ConclusionsOur data support the hypotheses that (i) large expansions occur prezygotically or in the very early embryo, (ii) large unmethylated alleles may be deleterious in stem cells, (iii) methylation can occur on alleles with>400 repeats very early in embryogenesis, and (iv) expansion and contraction may occur by different mechanisms. Our data also suggest that the threshold for stable methylation of FM alleles may be higher than previously thought. A higher threshold might explain why some carriers of FM alleles escape methylation. It may also provide a simple explanation for why silencing has not been observed in m...
Source: Molecular Autism - Category: Molecular Biology Source Type: research
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Source: Stem Cells - Category: Stem Cells Authors: Tags: Embryonic Stem Cells/Induced Pluripotent Stem Cells Source Type: research
This article is protected by copyright. All rights reserved. We have created robust FMR1‐luciferase reporter cell lines using genome editing. The reporter line faithfully reports endogenous FMR1 gene activation therefore will provide a critical resource for drug screening.
Source: Stem Cells - Category: Stem Cells Authors: Tags: Original Research Source Type: research
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