Fxr1 knockout mice show a striated muscle phenotype: implications for Fxr1p function in vivo

Abstract

FXR1 is one of the two known homologues of FMR1. FXR1 shares a high degree of sequence homology with FMR1 and also encodes two KH domains and an RGG domain, conferring RNA-binding capabilities. In comparison with FMRP, very little is known about the function of FXR1P in vivo. Mouse knockout (KO) models exist for both Fmr1 and Fxr2. To study the function of Fxr1 in vivo, we generated an Fxr1 KO mouse model. Homozygous Fxr1 KO neonates die shortly after birth most likely due to cardiac or respiratory failure. Histochemical analyses carried out on both skeletal and cardiac muscles show a disruption of cellular architecture and structure in E19 Fxr1 neonates compared with wild-type (WT) littermates. In WT E19 skeletal and cardiac muscles, Fxr1p is localized to the costameric regions within the muscles. In E19 Fxr1 KO littermates, in addition to the absence of Fxr1p, costameric proteins vinculin, dystrophin and alpha-actinin were found to be delocalized. A second mouse model (Fxr1 + neo), which expresses strongly reduced levels of Fxr1p relative to WT littermates, does not display the neonatal lethal phenotype seen in the Fxr1 KOs but does display a strongly reduced limb musculature and has a reduced life span of approximately 18 weeks. The results presented here point towards a role for Fxr1p in muscle mRNA transport/translation control similar to that seen for Fmrp in neuronal cells.

Regulation of monocyte induced cell migration by the RNA binding protein, FXR1

“…1,2 The RNA binding protein, Fragile-X-Mental-Retardation-syndrome-Related protein 1 (FXR1) [3][4][5] is overexpressed and associated with poor clinical outcomes in multiple cancers. 6 FXR1 is similar to Fragile-X-Mental Retardation Protein 1 (FMR1), 4,[7][8][9][10][11][12][13][14] and is implicated at multiple levels of post-transcriptional control, including translation, mRNA stability and transport.…”

“…6 FXR1 is similar to Fragile-X-Mental Retardation Protein 1 (FMR1), 4,[7][8][9][10][11][12][13][14] and is implicated at multiple levels of post-transcriptional control, including translation, mRNA stability and transport. 7-10, 12-13, 15-18 FXR1 is associated with negative regulation of specific growth factor and cytokine mRNAs in myocytes 5,[19][20][21][22] and macrophages, 16 which can control development, cell differentiation and cell state specific functions. However, our previous studies demonstrated that a spliced isoform of FXR1, FXR1a, promotes specific mRNA translation independent of RNA levels, in association with an altered microRNP (microRNA-protein complex), in distinct conditions, such as oocytes and quiescent (> 24 h, 30-48 h extended serum-starved) mammalian cells.…”

“…Cytokines like TNFa are transcribed and detected in these conditions; however, the role of FXR1 in regulating specific mRNA levels and expression in serum grown and in early 24 h serum-starved THP1 cells remains to be outlined. Given the effect of FXR1 on cell differentiation 5,[20][21][22] and cancer 6 and its regulation of TNFa cytokine mRNA expression in quiescent, extended serum-starved cells, we examined the role of FXR1 in regulating mRNA levels in serum grown cells and in early (24 h) serum-starved monocytic leukemic cells.…”

The RNA binding protein FXR1 is a new driver in the 3q26-29 amplicon and predicts poor prognosis in human cancers

“…Nevertheless, few RBPs have been identified as oncogenes or tumor suppressors and clinical implications of these cancer related RBPs is largely unknown. FXR1 is highly expressed in vertebrate muscle cells and FXR1 knockout mice die early during embryogenesis, suggesting an essential role for FXR1 in development (12). In this study, we examined whether RNA binding protein FXR1 is a regulator of tumor progression in nonsmall cell lung cancer (NSCLC) and a driver of the 3q amplicon.…”

Le syndrome de l’X fragile : une protéine absente et 1001 ARNm déboussolés

“…Les muscles striés cardiaque et squelettiques constituent une exception, puisque seule FXR1P est exprimée sous une forme longue particulière de 82-84 kDa [8]. Les souris Fxr1 -/-meurent quelques minutes après leur naissance, vraisemblablement à cause d'un développement anormal des muscles cardiaque et respiratoires [9]. En effet, FXR1P est nécessaire au développement des muscles comme nous l'avons montré récemment chez la grenouille [10].…”