Trends in Biochemical Sciences
New insights into fragile X syndrome: from molecules to neurobehaviors
Section snippets
Features of FMRP
FMRP is widely expressed in fetal and adult tissues, with the most abundant expression in brain and testes [4]. FMRP, and its autosomal paralogs the fragile-X-related protein FXR1P and FXR2P, consists of a small family of RNA-binding proteins (fragile X-related gene family) 5, 6. These proteins share >60% amino acid identity and contain two types of RNA-binding motifs: two ribonucleoprotein K homology domains (KH domains) and a cluster of arginine and glycine residues (RGG box). Owing to their
FMRP–mRNP complex: protein components, mRNA ligands and its role in translation
The majority of cytoplasmic FMRP is a component of a large mRNP complex, which contains multiple proteins and FMRP and/or mRNA ligands. Using a murine cell culture system expressing epitope-tagged FMRP, several protein components of the FMRP–mRNP complex that are co-immunoprecipitated with tagged FMRP have been identified, including FXR1P, FXR2P, nucleolin and YB1/p50 16, 17. Also through co-immunoprecipitation, using an antibody against Pur α, FMRP was found to be part of an mRNP complex
Physiological consequences of FMRP deficiency in the brain
To improve our understanding of the physiological functions of FMRP in the brain, both the Fmr1-knockout mouse and the recently developed dfmr1-mutant flies have been studied 3, 9, 15, 31, 40, 41. Previous research has shown that the Fmr1-knockout mouse has subtle defects in behavior and spatial learning compared with wild-type mice [3]. Using various experimental paradigms, the Fmr1-knockout mouse has been reported to display increased sensitivity to audiogenic epileptic seizures, and greater
Concluding remarks
Recent advances in fragile X syndrome have provided new avenues to understand the molecular pathogenesis of this disease. Identification of FMRP mRNA ligands and the RNA structure required for the FMRP–RNA interaction will help to understand the role of FMRP in protein synthesis during neuronal development. The establishment of fly models will be very useful and important to dissect the physiological pathways regulated by FMRP using genetic approaches. Moreover, finding enhanced mGluR-LTD in
Acknowledgements
We thank Stephanie Ceman, Yue Feng, Tracie Rosser and Daniela Zarnescu for critical reading of the article, and Janelle Clark for assistance. Supported by NIH grants R37 HD20521 and PO1 HD35576. P.J. is supported by Rett Syndrome Research Foundation.
Glossary
Glossary
- Dendritic spine dysgenesis:
- misregulation of dendritic spine formation during the development of nervous system.
- Fragile site:
- specific chromosomal regions that form gaps, breaks and rearrangements when cells are cultured under conditions that inhibit DNA replication.
- G-quartet:
- hydrogen-bonded structures formed from four guanosine residues in a square-planar array that are stabilized preferentially by K+ and disrupted by the presence of Li+.
- Macroorchidism:
- the condition (as in fragile X syndrome) of
References (55)
FMRP associates with polyribosomes as an mRNP, and the I304N mutation of severe fragile X syndrome abolishes this association
Mol. Cell
(1997)Drosophila fragile X protein, DFXR, regulates neuronal morphology and function in the brain
Neuron
(2002)Identification of mouse YB1/p50 as a component of the FMRP-associated mRNP particle
Biochem. Biophys. Res. Commun.
(2000)Identification of mRNA/protein (mRNP) complexes containing Puralpha, mStaufen, fragile X protein, and myosin Va and their association with rough endoplasmic reticulum equipped with a kinesin motor
J. Biol. Chem.
(2002)Microarray identification of FMRP-associated brain mRNAs and altered mRNA translational profiles in fragile X syndrome
Cell
(2001)Fragile X mental retardation protein targets G quartet mRNAs important for neuronal function
Cell
(2001)Drosophila fragile X-related gene regulates the MAP1B homolog Futsch to control synaptic structure and function
Cell
(2001)Drosophila lacking dfmr1 activity show defects in circadian output and fail to maintain courtship interest
Neuron
(2002)A role for the Drosophila fragile x-related gene in circadian output
Curr. Biol.
(2002)- et al.
Fragile X mice develop sensory hyperreactivity to auditory stimuli
Neuroscience
(2001)