Novel isoforms of the fragile X related protein FXR1P are expressed during myogenesis

Abstract

The fragile X syndrome results from transcriptional silencing of the FMR1 gene and the absence of its encoded FMRP protein. Two autosomal homologues of the FMR1 gene, FXR1 and FXR2, have been identified and the overall structures of the corresponding proteins are very similar to that of FMRP. Using antibodies raised against FXR1P, we observed that two major protein isoforms of relative MW of 78 and 70 kDa are expressed in different mammalian cell lines and in the majority of mouse tissues. In mammalian cells grown in culture as well as in brain extracts, both P78and P70isoforms are associated with mRNPs within translating polyribosomes, similarly to their closely related FMRP homologues. In muscle tissues as well as in murine myoblastic cell lines induced to differentiate into myotubes, FXR1P78and P70isoforms are replaced by novel unpredicted isoforms of 81-84 kDa and a novel FXR1 exon splice variant was detected in muscle RNA. While P81-84isoforms expressed after fusion into myotubes in murine myoblast cell lines grown in culture are associated with polyribosomes, this is not the case when isolated from muscle tissues since they sediment with lower S values. Immunohistochemical studies showed coexpression of FMRP and FXR1P70and P78in the cytoplasm of brain neurons, while in muscle no FMRP was detected and FXR1P81-84were mainly localized to structures within the muscle contractile bands. The complex expression pattern of FXR1P suggests tissue-specific expression for the various isoforms of FXR1 and the differential expression of FMRP and FXR1Ps suggests that in certain types of cells and tissues, complementary functions may be fulfilled by the various FMRP family members.

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

“…5,6,16,[19][20][21][22]24 Our previous data demonstrated a role for an isoform of FXR1 in quiescent (extended > 24 h serum-starved) cells, in upregulating translation (independent of RNA level changes) of a critical cytokine, TNFa 17 that can promote monocyte functions, signaling and differentiation. 26,[28][29][30][31] In early (24 h) serumstarved THP1 acute monocytic leukemic cells, our data revealed altered gene expression mechanisms 33 that are distinct from those in quiescent (extended > 24 h serum-starved) cells.…”

“…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.…”

Expression of fragile X mental retardation protein and Fmr1 mRNA during folliculogenesis in the rat

“…Given the well-documented high expression of FMRP in testis and brain (Devys et al 1993, Tamanini et al 1997, Bakker et al 2000, and the lack of FMRP expression in skeletal muscle (Devys et al 1993, Khandjian et al 1998, Bakker et al 2000, these tissues …”

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

“…La répartition tissulaire et les degrés d'expression de FXR1P suivent ceux de O v a i r e R e i n I n t e s t i n g r ê l e C ô l o n R a t e U t é r u s E s t o m a c P o u m o n F o i e P e a u V e s s i e C oe u r P é r i t o i n e M u s c l e A B FMRP. 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].…”