The School of Molecular and Cellular Biology at the University of Illinois at Urbana-Champaign

The Fragile X Mental Retardation Protein (FMRP) is an mRNA binding protein that is required for normal cognition; its absence causes the most common form of inherited mental retardation, fragile X syndrome. FMRP binds a large collection of mRNAs and regulates their transport and translation. We are interested in understanding how these processes are regulated, which we will determine by addressing the following questions:

1. Does FMRP bind its mRNA cargoes in the nucleus and what are the molecular requirements for this association?
2. Does arginine methylation of the primary RNA binding motif in FMRP (the RGG box) modulate RNA binding and which enzymes mediate methylation?
3. How does FMRP regulate translation of its bound mRNAs through the microRNA pathway?

We published the first evidence that FMRP’s primary RNA binding motif, the RGG box is methylated in cells and that this methylation inhibits RNA binding in vitro (Stetler, et al. 2006). We now have evidence that protein arginine methyl transferase (PRMT) 1 and PRMT3 act on FMRP and that by reducing methylation of FMRP, there is more FMRP on polyribosomes suggesting that more mRNAs are bound and translated (Blackwell and Ceman,2010).

FMRP also functions in the microRNA pathway, associating with its component protein Dicer, as well as with precursor and mature microRNAs. We have evidence that phosphorylation of FMRP inhibits association with Dicer, resulting in an accumulation of precursor microRNAs with FMRP. (Cheever and Ceman, 2009).

Taken together, we propose a model in which FMRP enters the nucleus to bind its RNA cargoes and is methylated by PRMT1 to modulate its mRNA binding ability. We also propose that FMRP binds precursor microRNAs in the nucleus. RNA-bound FMRP is exported to the cytoplasm where phosphorylation regulates mRNA translation by modulating association with the nuclease Dicer. Like its autosomal paralog FXR1, we propose that FMRP requires microRNAs to activate translation. Since phosphorylation of FMRP leads to loss of Dicer association and a corresponding increase in precursor microRNAs, we propose that phosphorylation of FMRP leads to translation suppression through loss of activating microRNAs.

Fig.1. FMRP-RNA binding model. FMRP enters the nucleus where RGG box methylation by PRMT1 modulates mRNA binding. FMRP binds nascent transcripts and precursor microRNAs and is exported from the nucleus by Tap/NXF1 and exportin 5, respectively. In the cytoplasm, FMRP is methylated by PRMT3, which prevents further mRNA binding. FMRP associates with Dicer, cleaving precursors to microRNAs that activate translation. Phosphorylation of FMRP inhibits Dicer association.

Representative Publications

Kim, M. and S. Ceman. 2012. Fragile X Mental Retardation Protein: Past, Present and Future. Current Protein & Peptide Science. In press

Blackwell, E. and Ceman, S. 2012. Arginine methylation of RNA binding proteins regulates cell function and differentiation. Molecular Reproductive Physiology. In press.

Winograd, C. and Ceman, S. 2011. Fragile X family members have important and non-overlapping functions. Biomolecular Concepts. accepted

Blackwell. E. and Ceman, S. 2011. Novel regulatory function of region proximal to RGG box in Fragile X Mental Retardation Protein. J. Cell Science. 124: 3060-3065.

Ceman, S. and Saugstad, J. 2011. MicroRNAs: Meta-controllers of gene expression in synaptic activity emerge as genetic and diagnostic markers of human disease. Pharmacology and Therapeutics. 130(1): 26-37.

Cheever, A., Blackwell, E., Ceman, S. 2010. Fragile X protein family member FXR1P is regulated by microRNAs. RNA.18 (8): 1530-1539

Blackwell, E. , Zhang, X. and Ceman, S. 2010. Arginines of the RGG box regulate FMRP association with polyribosomes and mRNA. Hum. Mol. Gen.. 19(7): 1314-1323. PMC2838539.

Cheever, A. and Ceman. S. 2009. Translation regulation of mRNAs by the fragile X family of proteins through the microRNA pathway. RNA Biology.6:2.

Cheever, A. and Ceman. S. 2009. Phosphorylation of FMRP inhibits association with Dicer. RNA. 15(3): 362-366.

Kim, M., Bellini, M., Ceman, S. 2009. Fragile X mental retardation protein FMRP binds mRNAs in the nucleus. MCB. 29(1): 214-228.

Winograd, C., Clayton, D. Ceman, S. 2008. Expression of fragile X mental retardation protein within the vocal control system of developing and adult male zebra finches. Neurosci. 157(1):132-142.

Narayanan, U., Nalavadi, V., Nakamoto, M., Thomas, G., Ceman, S., Bassell, G. J., Warren, S. T. 2008. S6K1 phosphorylates and regulates FMRP with the neuronal protein synthesis-dependent mTOR signaling cascade. J. Biol. Chem. 283(27):18478-82.

Narayanan, U., Nalavadi, V., Nakamoto, M., Pallas, D., Ceman, S., Bassell, G. J., and Warren, S.T. 2007. FMRP phosphorylation reveals an immediate-early signaling pathway triggered by groupI mGluR and mediated by PP2A. J. Neurosci., 27(52):14349–57. [Abstract] [Journal Cover]

Stetler, A. Winograd, C., Sayegh, J., Cheever, A., Patton, E., Zhang, X., Clarke, S., and Ceman, S. 2006. Identification and characterization of the methyl arginines in the fragile X mental retardation protein Fmrp. Hum. Mol. Genet., 15(1):87–96. [Abstract]

Complete Publications List