Identification of FMRP target mRNAs in the developmental brain: FMRP might coordinate Ras/MAPK, Wnt/β-catenin, and mTOR signaling during corticogenesis

Casingal, Cristine R.; Kikkawa, Takako; Inada, Hitoshi; Sasaki, Yukio; Osumi, Noriko

doi:10.1186/s13041-020-00706-1

Cited by 47 publications

(31 citation statements)

References 86 publications

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“…MET is a receptor tyrosine kinase that directly modulates WNT/β-catenin signaling (Kim et al, 2013) in line with the enrichment of transcripts of WNT signaling pathway (p = .001, p adjusted = .0228, GSEA) in FXS hASTRO genes (Figure 4c). These results were consistent with previous studies showing that the WNT/β-catenin signaling pathway is affected and involved in altered fate specification of neural progenitors in FXS (Casingal et al, 2020;Luo et al, 2010).…”

Section: Transcriptome Analysis Of Fxs Cells During Astrocyte Differentiationsupporting

confidence: 94%

Urokinase plasminogen activator mediates changes in human astrocytes modeling fragile X syndrome

Peteri

Pitkonen

Toma

et al. 2021

Glia

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The function of astrocytes intertwines with the extracellular matrix, whose neuron and glial cell-derived components shape neuronal plasticity. Astrocyte abnormalities have been reported in the brain of the mouse model for fragile X syndrome (FXS), the most common cause of inherited intellectual disability, and a monogenic cause of autism spectrum disorder. We compared human FXS and control astrocytes generated from human induced pluripotent stem cells and we found increased expression of urokinase plasminogen activator (uPA), which modulates degradation of extracellular matrix. Several pathways associated with uPA and its receptor function were activated in FXS astrocytes.Levels of uPA were also increased in conditioned medium collected from FXS hiPSCderived astrocyte cultures and correlated inversely with intracellular Ca 2+ responses to activation of L-type voltage-gated calcium channels in human astrocytes. Increased uPA augmented neuronal phosphorylation of TrkB within the docking site for the phospholipase-Cγ1 (PLCγ1), indicating effects of uPA on neuronal plasticity. Gene expression changes during neuronal differentiation preceding astrogenesis likely contributed to properties of astrocytes with FXS-specific alterations that showed specificity by not affecting differentiation of adenosine triphosphate (ATP)-responsive astrocyte Ulla-Kaisa Peteri and Juho Pitkonen contributed equally to this study.

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Section: Transcriptome Analysis Of Fxs Cells During Astrocyte Differentiationsupporting

confidence: 94%

Urokinase plasminogen activator mediates changes in human astrocytes modeling fragile X syndrome

Peteri

Pitkonen

Toma

et al. 2021

Glia

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“…We further analyzed the potential mechanism of LRRN4 in CRC malignant phenotype by using the WGCNA and DAVID. Several signaling pathways were found to be regulated by LRRN4, including Ras signaling pathway, the mitogen-activated protein kinases (MAPK), and phosphoinositide-3 kinase (PI3K) pathways, which are known to correlate with the malignant phenotype of cancer cells [27][28][29][30][31]. However, there was no evidence suggesting that LRRN directly regulates these signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Prognostic Value and Biological Function of LRRN4 in Colorectal Cancer

Cheng

Chen

Long

et al. 2021

Preprint

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Background: Several nervous and nerve-related biomarkers have been detected in colorectal cancer (CRC) and can contribute to the progression of CRC. However, the role of leucine-rich repeat neuronal 4 (LRRN4), a recently identified neurogenic marker, in CRC remains unclear. Methods: We examined the expression and the clinical outcomes of LRRN4 in CRC from TCGA-COREAD mRNA-sequencing datasets and immunohistochemistry on the Chinese cohort. Furthermore, the colony formation, flow cytometry, wound healing assay and mouse xenograft models were used to investigate the biological significance of LRRN4 in CRC cell lines with LRRN4 knockdown or overexpression in vitro and in vivo. In addition, weighted co-expression network analysis and DAVID were used to explore the potential molecular mechanism. Results: We provide the first evidence that LRRN4 expression, at both the protein and mRNA level, was remarkable high in CRC compared to controls and positively correlated with the clinical outcome of CRC patients. Specifically, LRRN4 was an independent prognostic factor for progression-free survival and overall survival in CRC patients. Further functional experiments showed that LRRN4 promoted cell proliferation, cell DNA synthesis and cell migration and inhibited apoptosis. Knockdown of LRRN4 can correspondingly decrease these effects in vitro and can significantly suppress the growth of xenografts. Several biological functions and signaling pathways were regulated by LRRN4, including proteoglycans in cancer, glutamatergic synapse, Ras, MAPK and PI3K.Conclusions: Our results suggest that LRRN4 could be a biological and molecular determinant to stratify CRC patients into distinct risk categories, and mechanistically, this is likely attributable to LRRN4 in regulating several malignant phenotypes of neoplastic cells via cancer-related pathways.

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“…Hence in FXS, mGluR-LTD is decoupled from protein synthesis/mTOR activation. Interestingly in Fmr1 KO mice, mTOR phosphorylation is increased in embryonic neocortex and in postnatal hippocampus samples (Sharma et al, 2010;Casingal et al, 2020).…”

Section: Phosphatidylinositol-3-kinasesmentioning

confidence: 99%

Rett Syndrome and Fragile X Syndrome: Different Etiology With Common Molecular Dysfunctions

Bach

Shovlin

Moriarty

et al. 2021

Front. Cell. Neurosci.

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Rett syndrome (RTT) and Fragile X syndrome (FXS) are two monogenetic neurodevelopmental disorders with complex clinical presentations. RTT is caused by mutations in the Methyl-CpG binding protein 2 gene (MECP2) altering the function of its protein product MeCP2. MeCP2 modulates gene expression by binding methylated CpG dinucleotides, and by interacting with transcription factors. FXS is caused by the silencing of the FMR1 gene encoding the Fragile X Mental Retardation Protein (FMRP), a RNA binding protein involved in multiple steps of RNA metabolism, and modulating the translation of thousands of proteins including a large set of synaptic proteins. Despite differences in genetic etiology, there are overlapping features in RTT and FXS, possibly due to interactions between MeCP2 and FMRP, and to the regulation of pathways resulting in dysregulation of common molecular signaling. Furthermore, basic physiological mechanisms are regulated by these proteins and might concur to the pathophysiology of both syndromes. Considering that RTT and FXS are disorders affecting brain development, and that most of the common targets of MeCP2 and FMRP are involved in brain activity, we discuss the mechanisms of synaptic function and plasticity altered in RTT and FXS, and we consider the similarities and the differences between these two disorders.

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Identification of FMRP target mRNAs in the developmental brain: FMRP might coordinate Ras/MAPK, Wnt/β-catenin, and mTOR signaling during corticogenesis

Cited by 47 publications

References 86 publications

Urokinase plasminogen activator mediates changes in human astrocytes modeling fragile X syndrome

Urokinase plasminogen activator mediates changes in human astrocytes modeling fragile X syndrome

Prognostic Value and Biological Function of LRRN4 in Colorectal Cancer

Rett Syndrome and Fragile X Syndrome: Different Etiology With Common Molecular Dysfunctions

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