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"Nelson, David L."
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Ablation of Fmrp in adult neural stem cells disrupts hippocampus-dependent learning
Fragile X mental retardation is caused by mutations in the
FMRP
gene. Now, Xinyu Zhao and her colleagues show that deletion of Fmrp specifically in adult neural progenitor cells is sufficient to induce learning deficits in mice, whereas restoration of Fmrp only in neural progenitor cells in Fmrp-deficient mice restores learning.
Deficiency in fragile X mental retardation protein (FMRP) results in fragile X syndrome (FXS), an inherited form of intellectual disability. Despite extensive research, it is unclear how FMRP deficiency contributes to the cognitive deficits in FXS. Fmrp-null mice show reduced adult hippocampal neurogenesis. As Fmrp is also enriched in mature neurons, we investigated the function of Fmrp expression in neural stem and progenitor cells (aNSCs) and its role in adult neurogenesis. Here we show that ablation of Fmrp in aNSCs by inducible gene recombination leads to reduced hippocampal neurogenesis
in vitro
and
in vivo
, as well as markedly impairing hippocampus-dependent learning in mice. Conversely, restoration of Fmrp expression specifically in aNSCs rescues these learning deficits in Fmrp-deficient mice. These data suggest that defective adult neurogenesis may contribute to the learning impairment seen in FXS, and these learning deficits can be rectified by delayed restoration of Fmrp specifically in aNSCs.
Journal Article
Intercepting IRE1 kinase‐FMRP signaling prevents atherosclerosis progression
Fragile X Mental Retardation protein (FMRP), widely known for its role in hereditary intellectual disability, is an RNA‐binding protein (RBP) that controls translation of select mRNAs. We discovered that endoplasmic reticulum (ER) stress induces phosphorylation of FMRP on a site that is known to enhance translation inhibition of FMRP‐bound mRNAs. We show ER stress‐induced activation of Inositol requiring enzyme‐1 (IRE1), an ER‐resident stress‐sensing kinase/endoribonuclease, leads to FMRP phosphorylation and to suppression of macrophage cholesterol efflux and apoptotic cell clearance (efferocytosis). Conversely, FMRP deficiency and pharmacological inhibition of IRE1 kinase activity enhances cholesterol efflux and efferocytosis, reducing atherosclerosis in mice. Our results provide mechanistic insights into how ER stress‐induced IRE1 kinase activity contributes to macrophage cholesterol homeostasis and suggests IRE1 inhibition as a promising new way to counteract atherosclerosis.
Synopsis
Targeting IRE1 function and substrate(s) provides a novel therapeutic approach to atherosclerosis. We found a key role for IRE1‐mediated FMRP phosphorylation that suppresses the expression of cholesterol transporters and efferocytosis receptors in macrophages and promotes atherosclerosis progression.
FMRP is a novel IRE1 kinase substrate.
Lipid‐induced, IRE1‐mediated FMRP phosphorylation leads to post‐transcriptional suppression of cholesterol transporters and efferocytosis regulators.
Ablation of IRE1 kinase activity or suppression of FMRP expression enhances efferocytosis and cholesterol transport
in vitro
and
in vivo
.
IRE1 kinase inhibition by a small molecule inhibitor or genetic deletion of FMRP in macrophages alleviates atherosclerotic plaque formation.
Graphical Abstract
Targeting IRE1 function and substrate(s) provides a novel therapeutic approach to atherosclerosis. We found a key role for IRE1‐mediated FMRP phosphorylation that suppresses the expression of cholesterol transporters and efferocytosis receptors in macrophages and promotes atherosclerosis progression.
Journal Article
Recessive mutations in muscle-specific isoforms of FXR1 cause congenital multi-minicore myopathy
FXR1
is an alternatively spliced gene that encodes RNA binding proteins (FXR1P) involved in muscle development. In contrast to other tissues, cardiac and skeletal muscle express two FXR1P isoforms that incorporate an additional exon-15. We report that recessive mutations in this particular exon of
FXR1
cause congenital multi-minicore myopathy in humans and mice. Additionally, we show that while
Myf5
-dependent depletion of all FXR1P isoforms is neonatal lethal, mice carrying mutations in exon-15 display non-lethal myopathies which vary in severity depending on the specific effect of each mutation on the protein.
FXR1P is a RNA binding protein involved in muscle development. Here, the authors show that mutations in
FXR1
exon 15, which is alternatively spliced in muscle, cause multi-minicore myopathy in humans and in mouse models.
Journal Article
Stereoscopic Height and Wind Retrievals for Aerosol Plumes with the MISR INteractive eXplorer (MINX)
The Multi-angle Imaging SpectroRadiometer (MISR) instrument aboard the Terra satellite acquires imagery at 275-m resolution at nine angles ranging from 0deg (nadir) to 70deg off-nadir. This multi-angle capability facilitates the stereoscopic retrieval of heights and motion vectors for clouds and aerosol plumes. MISR's operational stereo product uses this capability to retrieve cloud heights and winds for every satellite orbit, yielding global coverage every nine days. The MISR INteractive eXplorer (MINX) visualization and analysis tool complements the operational stereo product by providing users the ability to retrieve heights and winds locally for detailed studies of smoke, dust and volcanic ash plumes, as well as clouds, at higher spatial resolution and with greater precision than is possible with the operational product or with other space-based, passive, remote sensing instruments. This ability to investigate plume geometry and dynamics is becoming increasingly important as climate and air quality studies require greater knowledge about the injection of aerosols and the location of clouds within the atmosphere. MINX incorporates features that allow users to customize their stereo retrievals for optimum results under varying aerosol and underlying surface conditions. This paper discusses the stereo retrieval algorithms and retrieval options in MINX, and provides appropriate examples to explain how the program can be used to achieve the best results.
Journal Article
Biochemical and genetic interaction between the fragile X mental retardation protein and the microRNA pathway
Fragile X syndrome is caused by a loss of expression of the fragile X mental retardation protein (FMRP). FMRP is a selective RNA-binding protein which forms a messenger ribonucleoprotein (mRNP) complex that associates with polyribosomes. Recently, mRNA ligands associated with FMRP have been identified. However, the mechanism by which FMRP regulates the translation of its mRNA ligands remains unclear. MicroRNAs are small noncoding RNAs involved in translational control. Here we show that
in vivo
mammalian FMRP interacts with microRNAs and the components of the microRNA pathways including Dicer and the mammalian ortholog of Argonaute 1 (AGO1). Using two different
Drosophila melanogaster
models, we show that AGO1 is critical for FMRP function in neural development and synaptogenesis. Our results suggest that FMRP may regulate neuronal translation via microRNAs and links microRNAs with human disease.
Journal Article
Stephen T. Warren 1953–2021
Stephen T. Warren was a key contributor to the 1991 discovery of an unstable trinucleotide repeat that expands in families and causes loss of function in fragile X syndrome.
Journal Article
Characterization and visualization of tandem repeats at genome scale
Tandem repeat (TR) variation is associated with gene expression changes and numerous rare monogenic diseases. Although long-read sequencing provides accurate full-length sequences and methylation of TRs, there is still a need for computational methods to profile TRs across the genome. Here we introduce the Tandem Repeat Genotyping Tool (TRGT) and an accompanying TR database. TRGT determines the consensus sequences and methylation levels of specified TRs from PacBio HiFi sequencing data. It also reports reads that support each repeat allele. These reads can be subsequently visualized with a companion TR visualization tool. Assessing 937,122 TRs, TRGT showed a Mendelian concordance of 98.38%, allowing a single repeat unit difference. In six samples with known repeat expansions, TRGT detected all expansions while also identifying methylation signals and mosaicism and providing finer repeat length resolution than existing methods. Additionally, we released a database with allele sequences and methylation levels for 937,122 TRs across 100 genomes.
A set of tools maps tandem repeats across complete genomes.
Journal Article
Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share phenotypic and pathologic overlap. Recently, an expansion of GGGGCC repeats in the first intron of C9orf72 was found to be a common cause of both illnesses; however, the molecular pathogenesis of this expanded repeat is unknown. Here we developed both Drosophila and mammalian models of this expanded hexanucleotide repeat and showed that expression of the expanded GGGGCC repeat RNA (rGGGGCC) is sufficient to cause neurodegeneration. We further identified Pur α as the RNA-binding protein of rGGGGCC repeats and discovered that Pur α and rGGGGCC repeats interact in vitro and in vivo in a sequence-specific fashion that is conserved between mammals and Drosophila. Furthermore, overexpression of Pur α in mouse neuronal cells and Drosophila mitigates rGGGGCC repeat-mediated neurodegeneration, and Pur α forms inclusions in the fly eye expressing expanded rGGGGCC repeats, as well as in cerebellum of human carriers of expanded GGGGCC repeats. These data suggest that expanded rGGGGCC repeats could sequester specific RNA-binding protein from their normal functions, ultimately leading to cell death. Taken together, these findings suggest that the expanded rGGGGCC repeats could cause neurodegeneration, and that Pur α may play a role in the pathogenesis of amyotrophic lateral sclerosis and frontotemporal dementia.
Journal Article