title: 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.
authors.affiliation: Department of Clinical Genetics, Erasmus University, Rotterdam, The Netherlands.
authors.forename: Edwin J
authors.initials: EJ
authors.lastname: Mientjes
authors.forename: Rob
authors.initials: R
authors.lastname: Willemsen
authors.forename: Laura L
authors.initials: LL
authors.lastname: Kirkpatrick
authors.forename: Ingeborg M
authors.initials: IM
authors.lastname: Nieuwenhuizen
authors.forename: Marianne
authors.initials: M
authors.lastname: Hoogeveen-Westerveld
authors.forename: Marcel
authors.initials: M
authors.lastname: Verweij
authors.forename: Surya
authors.initials: S
authors.lastname: Reis
authors.forename: Barbara
authors.initials: B
authors.lastname: Bardoni
authors.forename: Andre T
authors.initials: AT
authors.lastname: Hoogeveen
authors.forename: Ben A
authors.initials: BA
authors.lastname: Oostra
authors.forename: David L
authors.initials: DL
authors.lastname: Nelson
mesh_terms: D000818:Animals; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D051860:Fragile X Messenger Ribonucleoprotein 1; D006614:Hindlimb / Q000254:growth & development / Q000473:pathology; D008136:Longevity / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D017385:Sequence Homology
chemical_list: D003598:Cytoskeletal Proteins; D051860:Fragile X Messenger Ribonucleoprotein 1; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C497684:Fmr1 protein, mouse; C496283:Fxr1h protein, mouse