Differential expression of Fmr-1 mRNA and FMRP in female mice brain during aging

Abstract

Fragile X syndrome is caused by silencing of FMR-1 gene due to unusual expansion of CGG repeats (>200 repeats) and their hypermethylation in 5'-UTR. As a consequence, the expression of the RNA binding protein FMRP is stopped. Absence of this protein leads to several morphological and neurological symptoms. The symptoms of the syndrome in males are different than that in the females. We have previously reported that the Fmr1 gene is down regulated in males as a function of age. In the present communication, we have investigated expression of Fmr-1 mRNA, FMRP and analysis of interaction of trans-acting factors with E- and GC boxes in Fmr-1 promoter in female mouse brain as a function of age. Our Northern and Western blots data reveal that the level of Fmr-1 transcript decreases in adult as compared to young mouse but significantly increases in old age and that of FMRP decreases in brain of female old mouse as compared to young and adult age. The immunohistochemical analysis supported the results obtained from Western blot studies. Our EMSA data reveal that the intensity of USF1/USF2-E Box complex gradually increases during aging having significantly highest intensity in old age mouse whereas the intensity of alpha-Pal/Nrf1- GC-Box complex gradually decreases as a function of age. The increased intensity of the complex in old age mouse is correlated to higher level of Fmr-1 transcript in old age. The elevated level of Fmr-1 transcript in old mouse brain may be attributed to USF1/USF2 dependent increased transcription of Fmr-1 gene in old age and decrease in FMRP to altered translation of the transcript or high turn over of FMRP during aging. The present finding indicates age and sex as factors affecting the expression of Fmr-1 gene in mouse brain.