Discipline: Biological Sciences
Subcategory: Cell and Molecular Biology
Monica Chinea Diliz - University of Illinois Urbana Champaign
Co-Author(s): Stephanie Ceman, University of Illinois Urbana Champaign, Urbana, IL
Fragile X syndrome, the most common form of inherited cognitive impairment, affects 1 in 4,000 males and 1 in 8,000
females worldwide. Fragile X is caused by the absence of the RNA binding protein, Fragile X Mental Retardation Protein (FMRP). FMRP binds approximately 4% of brain mRNAs, although it remains unclear how FMRP regulates translation of its bound mRNAs. Recent work from our lab suggests that MOV10, an RNA helicase, may play a role in FMRP-mediated translational suppression. We previously showed that in Fmr1 knockout (KO) mice, a model to study Fragile X syndrome, MOV10 did not bind the common RNAs in the absence of FMRP, suggesting a role for FMRP in recruitment of MOV10 to RNAs. Our purpose is to understand the association of FMRP and MOV10 on their commonly bound brain RNAs, particularly to determine the localization and translational fate of these RNAs. We employed a primary neuron culture method, consisting of Fmr1 knockout (KO) and wild-type (WT) neurons as a control to test the hypothesis that FMRP binds RNAs and then recruits MOV10 to RNA granules. To determine localization of MOV10 relative to FMRP, we immunostained Fmr1 KO and WT neurons at different time points in vitro. Our results show that MOV10 localization is nuclear and cytoplasmic in day 0-1 in vitro and cytoplasmic at later time points. Moreover, in Fmr1 KO neurons, MOV10 is able to enter RNA granules, although it remains to be determined whether MOV10 and FMRP commonly bound RNAs are also found in granules, which we will address by performing single molecule fluorescence in situ hybridization (FISH). We predict that in the absence of FMRP, despite MOV10 localization to RNA granules, their will be a significant reduction in their commonly bound RNAs. By identifying the molecular mechanisms of FMRP on its mRNA ligands, and with binding partners such as MOV10, we can better develop viable therapeutic strategies to treat Fragile X syndrome, which is critically needed, as currently only palliative care options are available to Fragile X patients.
References: Crawford, D.C., Acuña, J.M., Sherman, S.L. 2001. FMR1 and the fragile x syndrome: human genome epidemiology review. Genet Med. 3(5):359-71. Kenny, P.J., Zhou, M., Kim, M., Skariah, G., Khetani, R.S., Drnevich, J., Arcila, K., Kosik, S., Ceman, S. 2014. MOV10 and FMRP regulate AGO2 association with microRNA recognition elements. Cell Reports. 9(5): 1729-1741.Not Submitted
Funder Acknowledgement(s): I thank S. Ceman for designing the experiments and her mentorship. Funding was provided by a NIMH grant to S. Ceman.
Faculty Advisor: Stephanie Ceman, email@example.com