The RNA-binding Protein Fragile X-related 1 Regulates Somite Formation inXenopus laevis

Abstract

Fragile X-related 1 protein (FXR1P) is a member of a small family of RNA-binding proteins that includes the Fragile X mental retardation 1 protein (FMR1P) and the Fragile X-related 2 protein (FXR2P). These proteins are thought to transport mRNA and to control their translation. While FMR1P is highly expressed in neurons, substantial levels of FXR1P are found in striated muscles and heart, which are devoid of FMRP and FXR2P. However, little is known about the functions of FXR1P. We have isolated cDNAs for Xenopus Fxr1 and found that two specific splice variants are conserved in evolution. Knockdown of xFxr1p in Xenopus had highly muscle-specific effects, normal MyoD expression being disrupted, somitic myotomal cell rotation and segmentation being inhibited, and dermatome formation being abnormal. Consistent with the absence of the long muscle-specific xFxr1p isoform during early somite formation, these effects could be rescued by both the long and short mRNA variants. Microarray analyses showed that xFxr1p depletion affected the expression of 129 known genes of which 50% were implicated in muscle and nervous system formation. These studies shed significant new light on Fxr1p function(s).

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

“…FXR1 depletion decreases the ability of monocytes to induce cell migration of neighboring cells FXR1 affects differentiation 5,[19][20][21] and macrophage physiology. 16 Moreover, FXR1 depletion resulted in altered expression of TNFa 23 and other cytokine and chemokine mRNAs 16 such as IL1b and CCL2 (Figs.…”

“…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.…”

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

“…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]. FXR2P apparaît comme le parent négligé de la famille : peu d'études lui sont consacrées.…”

“…Dès qu'un certain seuil de surcharge de FMRP est atteint, la protéine piège les ARNm et les réprime en les remisant dans des granules [15], jouant un rôle analogue à celui envisagé pour les granules neuronaux ( Figure 3C). Dans le muscle, FXR1P se retrouve aussi dans des structures granulaires semblables aux costamères [10] contenant des ARNm nécessaires à la synthèse locale de protéines sollicitées dans la contraction, la réparation et l'entretien du muscle. FXR1P pourrait ainsi participer à la régulation de la traduction de ces ARNm.…”