Here the authors show that a subset of m6A-modified mRNAs regulates the dynamics of RNA-granules, thus contributes to maternal mRNA decay.įragile 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. Maternal RNA degradation is critical for embryogenesis and is tightly controlled by maternal RNA-binding proteins. This mechanism may represent a general principle that regulated RNP-granules control RNA processing and normal development. Our findings reveal that sequence-specific mRNAs instruct FMR1-RNP granules to undergo a dynamic phase-switch, thus contributes to maternal mRNA decay.
The degradation of maternal mRNAs then causes granule de-condensation, allowing normal embryogenesis.
Importantly, this binding greatly induces FMR1 granule condensation to efficiently recruit unmodified mRNAs. The high-affinity binding largely depends on a hydrophobic network within FMR1 KH2 domain.
Here we show that Drosophila FMR1 preferentially binds mRNAs containing m6A-marked “AGACU” motif with high affinity to contributes to maternal RNA degradation. However, how FMR1 recognizes target mRNAs and how FMR1-RNP granule assembly/disassembly regulates FMR1-associated mRNAs remain elusive. Fragile X mental-retardation protein (FMR1) binds target mRNAs to form ribonucleoprotein (RNP) complexes/granules that control various biological processes, including early embryogenesis. These developing animal models will provide a sophisticated resource in which the deficits in complex functions of perception, action, and cognition in the human disorder are accurately reflected and aid in the successful translation of novel therapeutics and interventions to the clinic setting. This review will describe the status and rationale in the development, validation, and utility of three emerging animal model systems for FXS, namely the nonhuman primate (NHP), Mongolian gerbil, and chicken. While current FXS animal models contribute their own unique understanding to the molecular, cellular, physiological, and behavioral deficits associated with FXS, no single animal model is able to fully recreate the FXS phenotype. Despite considerable progress in our understanding of FXS, safe, effective, and reliable treatments that either prevent or reduce the severity of the FXS phenotype have not been approved. Individuals with Fragile X syndrome (FXS), the most common heritable form of intellectual disability, have a full-mutation sequence (>200 CGG repeats) which brings about transcriptional silencing of FMR1 and loss of FMR protein (FMRP). These studies have the potential to aid the discovery of pharmacological therapies for FXS.įragile X encompasses a range of genetic conditions, all of which result as a function of changes within the FMR1 gene and abnormal production and/or expression of the FMR1 gene products. In this review, we present very recent Drosophila studies investigating FMRP functions at genetic, cellular, molecular, and electrophysiological levels in addition to research on pharmacological treatments in the fly model. Drosophila has been widely used to investigate FMR1 functions at genetic, cellular, and molecular levels since dFMR1 mutants have many phenotypes in common with the wide spectrum of FMR1 functions that underlay the disease. This enables a much easier approach for FMR1 genetic studies.
Humans also carry the FXR1 and FXR2 paralogs of FMR1 while flies have only one FMR1 gene, here called dFMR1, sharing the same level of sequence homology with all three human genes, but functionally most similar to FMR1. Most cases of FXS are caused by silencing of FMR1 due to CGG expansions in the 5′-UTR of the gene. The gene responsible for FXS is Fragile X Mental Retardation gene 1 (FMR1) encoding the Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein involved in RNA metabolism and modulating the expression level of many targets. Intellectual disability (ID) and autism are hallmarks of Fragile X Syndrome (FXS), a hereditary neurodevelopmental disorder.
0 kommentar(er)
