Nuclear Fragile X Mental Retardation Protein is localized to Cajal bodies.

TitleNuclear Fragile X Mental Retardation Protein is localized to Cajal bodies.
Publication TypeJournal Article
Year of Publication2013
AuthorsDury AY, Fatimy REl, Tremblay S, Rose TM, Côté J, De Koninck P, Khandjian EW
JournalPLoS Genet
Volume9
Issue10
Paginatione1003890
Date Published2013 Oct
ISSN1553-7404
KeywordsAnimals, Cell Nucleus, Coiled Bodies, Fragile X Mental Retardation Protein, Fragile X Syndrome, Gene Expression Regulation, Humans, Mice, Neurons, Protein Isoforms, Ribonucleoproteins, RNA, Messenger, RNA-Binding Proteins
Abstract

Fragile X syndrome is caused by loss of function of a single gene encoding the Fragile X Mental Retardation Protein (FMRP). This RNA-binding protein, widely expressed in mammalian tissues, is particularly abundant in neurons and is a component of messenger ribonucleoprotein (mRNP) complexes present within the translational apparatus. The absence of FMRP in neurons is believed to cause translation dysregulation and defects in mRNA transport essential for local protein synthesis and for synaptic development and maturation. A prevalent model posits that FMRP is a nucleocytoplasmic shuttling protein that transports its mRNA targets from the nucleus to the translation machinery. However, it is not known which of the multiple FMRP isoforms, resulting from the numerous alternatively spliced FMR1 transcripts variants, would be involved in such a process. Using a new generation of anti-FMRP antibodies and recombinant expression, we show here that the most commonly expressed human FMRP isoforms (ISO1 and 7) do not localize to the nucleus. Instead, specific FMRP isoforms 6 and 12 (ISO6 and 12), containing a novel C-terminal domain, were the only isoforms that localized to the nuclei in cultured human cells. These isoforms localized to specific p80-coilin and SMN positive structures that were identified as Cajal bodies. The Cajal body localization signal was confined to a 17 amino acid stretch in the C-terminus of human ISO6 and is lacking in a mouse Iso6 variant. As FMRP is an RNA-binding protein, its presence in Cajal bodies suggests additional functions in nuclear post-transcriptional RNA metabolism. Supporting this hypothesis, a missense mutation (I304N), known to alter the KH2-mediated RNA binding properties of FMRP, abolishes the localization of human FMRP ISO6 to Cajal bodies. These findings open unexplored avenues in search for new insights into the pathophysiology of Fragile X Syndrome.

DOI10.1371/journal.pgen.1003890
Alternate JournalPLoS Genet.
PubMed ID24204304
PubMed Central IDPMC3814324
Grant List / / Canadian Institutes of Health Research / Canada

Funding

Our research endeavors are made possible by the following agencies:

Canadian Institutes of Health Research - Instituts de recherche en santé du Canada Fonds de recherche du Québec – Nature et technologies (FRQNT)Fonds de la recherche en santé du Québec NARSAD Natural Sciences and Engineering Research Council of Canada (NSERC) - Conseil de recherche en sciences naturelles et en génie du Canada (CRSNG)innovation.caHuman Frontier Science Program