Fragile X family members have important and non-overlapping functions

Winograd, Claudia; Ceman, Stephanie

doi:10.1515/bmc.2011.033

Cited by 9 publications

(8 citation statements)

References 104 publications

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“…Fragile X mental retardation protein is localized to the synapse upon metabotropic glutamate receptor activation, where it functions to target dendritic mRNAs and regulates translation under specific physiological conditions (Jin and Warren, 2003;Antar et al, 2004; Figure 2A). FMRP, as well as paralogs FXR1 and FXR2, are known to homo-and hetero-dimerize via coiled-coil motifs, although the functional consequences of this are unknown (Winograd and Ceman, 2011; Figure 1D). Lack of FMRP produces Fragile X Mental Retardation in humans, and in the mouse model of the disease, neural spine morphology is disrupted and forms excessively long and thin filopodia-like structures (Nimchinsky et al, 2001).…”

Section: Rna-binding Proteins That Contain Coiled-coil Motifs Are Ovementioning

confidence: 99%

Coiled-Coil Motifs of RNA-Binding Proteins: Dynamicity in RNA Regulation

Ford

Fioriti

2020

Front. Cell Dev. Biol.

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Neuronal granules are biomolecular condensates that concentrate high quantities of RNAs and RNA-related proteins within neurons. These dense packets of information are trafficked from the soma to distal sites rich in polysomes, where local protein synthesis can occur. Movement of neuronal granules to distal sites, and local protein synthesis, play a critical role in synaptic plasticity. The formation of neuronal granules is intriguing; these granules lack a membrane and instead phase separate due to protein and RNA interactions. Low complexity motifs and RNA binding domains are highly prevalent in these proteins. Here, we introduce the role that coiled-coil motifs play in neuronal granule proteins, and investigate the structure-function relationship of coiled-coil proteins in RNA regulation. Interestingly, low complexity domains and coiled-coil motifs are highly dynamic, allowing for increased functional response to environmental influences. Finally, biomolecular condensates have been suggested to drive the formation of toxic, neurodegenerative proteins such as TDP-43 and tau. Here, we review the conversion of coiled-coil motifs to amyloid structures, and speculate a role that neuronal granules play in coiled-coil to amyloid conversions of neurodegenerative proteins.

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Section: Rna-binding Proteins That Contain Coiled-coil Motifs Are Ovementioning

confidence: 99%

Coiled-Coil Motifs of RNA-Binding Proteins: Dynamicity in RNA Regulation

Ford

Fioriti

2020

Front. Cell Dev. Biol.

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“…The disease results from a developmentally regulated silencing of the Fragile X (FX) Mental Retardation Protein (FMRP) [1], an RNA-binding protein essential for proper synaptic architecture and plasticity [2]. Research models of FX include human neural progenitor cells taken from aborted fetuses [3,4] and FMR1 knockout (KO) animals that share some phenotypes with humans [5][6][7]. The FX phenotype is associated with several cellular defects including abnormal dendritic spine morphology, nonsense-mediated mRNA decay and altered intrinsic neuronal properties [8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Impaired Functional Connectivity Underlies Fragile X Syndrome

Gildin

Rauti

Vardi

et al. 2022

IJMS

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Fragile X syndrome (FXS), the most common form of inherited intellectual disability, is caused by a developmentally regulated silencing of the FMR1 gene, but its effect on human neuronal network development and function is not fully understood. Here, we isolated isogenic human embryonic stem cell (hESC) subclones—one with a full FX mutation and one that is free of the mutation (control) but shares the same genetic background—differentiated them into induced neurons (iNs) by forced expression of NEUROG-1, and compared the functional properties of the derived neuronal networks. High-throughput image analysis demonstrates that FX-iNs have significantly smaller cell bodies and reduced arborizations than the control. Both FX- and control-neurons can discharge repetitive action potentials, and FX neuronal networks are also able to generate spontaneous excitatory synaptic currents with slight differences from the control, demonstrating that iNs generate more mature neuronal networks than the previously used protocols. MEA analysis demonstrated that FX networks are hyperexcitable with significantly higher spontaneous burst-firing activity compared to the control. Most importantly, cross-correlation analysis enabled quantification of network connectivity to demonstrate that the FX neuronal networks are significantly less synchronous than the control, which can explain the origin of the development of intellectual dysfunction associated with FXS.

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“…They are highly homologous and bind target transcripts through two central KH domains. FMRP and FXR1P also display a C-terminal arginine–glycine–glycine (RGG) box that may be involved in RNA binding as well as homologous and heterologous interactions with other RBPs ( Siomi et al, 1994 ; Winograd and Ceman, 2011 ). FMRP interacts with argonaute 2 and remodels the ARE complex to activate translation upon serum starvation ( Vasudevan and Steitz, 2007 ).…”

Section: Rna-binding Proteins Involved In Skeletal Muscle Development Regeneration and Diseasementioning

confidence: 99%

RNA-Binding Proteins in the Post-transcriptional Control of Skeletal Muscle Development, Regeneration and Disease

Shi

Grifone

2021

Front. Cell Dev. Biol.

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Embryonic myogenesis is a temporally and spatially regulated process that generates skeletal muscle of the trunk and limbs. During this process, mononucleated myoblasts derived from myogenic progenitor cells within the somites undergo proliferation, migration and differentiation to elongate and fuse into multinucleated functional myofibers. Skeletal muscle is the most abundant tissue of the body and has the remarkable ability to self-repair by re-activating the myogenic program in muscle stem cells, known as satellite cells. Post-transcriptional regulation of gene expression mediated by RNA-binding proteins is critically required for muscle development during embryogenesis and for muscle homeostasis in the adult. Differential subcellular localization and activity of RNA-binding proteins orchestrates target gene expression at multiple levels to regulate different steps of myogenesis. Dysfunctions of these post-transcriptional regulators impair muscle development and homeostasis, but also cause defects in motor neurons or the neuromuscular junction, resulting in muscle degeneration and neuromuscular disease. Many RNA-binding proteins, such as members of the muscle blind-like (MBNL) and CUG-BP and ETR-3-like factors (CELF) families, display both overlapping and distinct targets in muscle cells. Thus they function either cooperatively or antagonistically to coordinate myoblast proliferation and differentiation. Evidence is accumulating that the dynamic interplay of their regulatory activity may control the progression of myogenic program as well as stem cell quiescence and activation. Moreover, the role of RNA-binding proteins that regulate post-transcriptional modification in the myogenic program is far less understood as compared with transcription factors involved in myogenic specification and differentiation. Here we review past achievements and recent advances in understanding the functions of RNA-binding proteins during skeletal muscle development, regeneration and disease, with the aim to identify the fundamental questions that are still open for further investigations.

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Fragile X family members have important and non-overlapping functions

Cited by 9 publications

References 104 publications

Coiled-Coil Motifs of RNA-Binding Proteins: Dynamicity in RNA Regulation

Coiled-Coil Motifs of RNA-Binding Proteins: Dynamicity in RNA Regulation

Impaired Functional Connectivity Underlies Fragile X Syndrome

RNA-Binding Proteins in the Post-transcriptional Control of Skeletal Muscle Development, Regeneration and Disease

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