title: Generation and characterization of an Nxf7 knockout mouse to study NXF5 deficiency in a patient with intellectual disability.
abstract: Members of the Nuclear eXport Factor (NXF) family are involved in the export of mRNA from the nucleus to the cytoplasm, or hypothesized to play a role in transport of cytoplasmic mRNA. We previously reported on the loss of NXF5 in a male patient with a syndromic form of intellectual disability. To study the functional role of NXF5 we identified the mouse counterpart. Based on synteny, mouse Nxf2 is the ortholog of human NXF5. However, we provide several lines of evidence that mouse Nxf7 is the actual functional equivalent of NXF5. Both Nxf7 and NXF5 are predominantly expressed in the brain, show cytoplasmic localization, and present as granules in neuronal dendrites suggesting a role in cytoplasmic mRNA metabolism in neurons. Nxf7 was primarily detected in the pyramidal cells of the hippocampus and in layer V of the cortex. Similar to human NXF2, mouse Nxf2 is highly expressed in testis and shows a nuclear localization. Interestingly, these findings point to a different evolutionary path for both NXF genes in human and mouse. We thus generated and validated Nxf7 knockout mice, which were fertile and did not present any gross anatomical or morphological abnormalities. Expression profiling in the hippocampus and the cortex did not reveal significant changes between wild-type and Nxf7 knockout mice. However, impaired spatial memory was observed in these KO mice when evaluated in the Morris water maze test. In conclusion, our findings provide strong evidence that mouse Nxf7 is the functional counterpart of human NXF5, which might play a critical role in mRNA metabolism in the brain.
authors.affiliation: Human Genome Laboratory, VIB Center for the Biology of Disease, Leuven, Belgium.
authors.forename: Lieselot
authors.initials: L
authors.lastname: Vanmarsenille
authors.forename: Jelle
authors.initials: J
authors.lastname: Verbeeck
authors.forename: Stefanie
authors.initials: S
authors.lastname: Belet
authors.forename: Anton J
authors.initials: AJ
authors.lastname: Roebroek
authors.forename: Tom
authors.initials: T
authors.lastname: Van de Putte
authors.forename: Joke
authors.initials: J
authors.lastname: Nevelsteen
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Callaerts-Vegh
authors.forename: Rudi
authors.initials: R
authors.lastname: D'Hooge
authors.forename: Peter
authors.initials: P
authors.lastname: Marynen
authors.forename: Guy
authors.initials: G
authors.lastname: Froyen
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D003594:Cytoplasmic Granules / Q000378:metabolism / Q000648:ultrastructure; D004195:Disease Models, Animal; D018703:Founder Effect; D015870:Gene Expression; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D018782:Maze Learning; D008568:Memory; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D029543:Nucleocytoplasmic Transport Proteins / Q000235:genetics* / Q000378:metabolism; D009928:Organ Specificity; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D013737:Testis / Q000378:metabolism
chemical_list: C443839:NXF5 protein, human; D029543:Nucleocytoplasmic Transport Proteins; C502321:Nxf2 protein, mouse; C502322:Nxf7 protein, mouse; D016601:RNA-Binding Proteins