Mice with targeted deletion of Nxf7, the murine ortholog of the clinically implicated NXF5, display impaired hippocampal learning and neuroplasticity

ABSTRACT: Members of the Nuclear mRNA Export Factor (NXF) family are implicated in nuclear export and/or cytoplasmic transport of mRNAs in eukaryotic cells. We previously proposed NXF5 to be involved in cognitive development and aimed to study its functional role further using a mouse model. The syntenic region of the human Xcen-GLA-NXF5-NXF2-NXF3-BEX4-Xqter in the mouse is Xcen-Gla-Nxf2-Nxf7-Nxf3-Bex4-Xqter strongly indicating that mouse Nxf2 is the homolog of human NXF5. However, our functional analyses demonstrated that mouse Nxf7 is actually the functional homolog of NXF5. Both orthologs are expressed in brain, although at low levels, show predominant cytoplasmic localization, and present a granular staining in neuronal dendrites, all indicative for a role in cytoplasmic mRNA transport or metabolism. The mouse and human Nxf2/NXF2 proteins on the other hand, show highest expression in testis, and mostly nuclear staining with incorporation in the nuclear membrane, suggesting a predominant role in nuclear mRNA export. Based on these findings we generated an Nxf7 knockout mouse, which was viable and fertile and no gross anatomical changes or morphological brain abnormalities were detected. Detailed behavioral analysis demonstrated that Nxf7 KO mice displayed a deficit in hippocampus-dependent spatial learning and memory. At the cellular level, this was accompanied by impaired hippocampal long-term potentiation, but normal long-term depression, suggesting a severe functional imbalance in NMDA-dependent synaptic plasticity. In conclusion, the present findings indicate that NXF5, and its murine ortholog Nxf7, play a crucial role in neurocognitive (memory) functions, and explain why its deletion leads to intellectual disability. Two male wild type (WT1 and WT2) and two Nxf7 knockout (KO1 and KO2) mice were used in each hybridization experiment (hippocampus or cortex). A loop-design hybridization scheme (WT1/KO1, KO1/WT2, WT2/KO2 and KO2/WT1) was performed for each experiment so as to have each sample labeled once with Cy5 and once with Cy3, and hybridised to both samples of the other genotype (WT or KO). Hybridization was done on Agilent Mouse Whole Genome arrays according to the manufacturerM-bM-^@M-^Ys procedures.

ORGANISM(S): Mus musculus

SUBMITTER: Joke Allemeersch 

PROVIDER: E-GEOD-29541 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress