“The Fmr1 gene encoding the fragile X protein is identified by positional cloning.”

The fragile X protein (FMRP) is a selective RNA-binding protein that governs normal brain function and development, since the lack of FMRP causes fragile X syndrome, the most frequent form of familial mental retardation. Discovering how FMRP functions to control neuronal function and development is the goal of many research teams, including ours. Our paper is the first to show that purified FMRP can act as a protein synthesis inhibitor by binding to its mRNA ligands in an in vitro translation system, providing the first biochemical evidence of FMRP’s function. In the same year, several groups identified mRNA ligands for FMRP. These studies served as a breakthrough in the fragile X field and led to extensive studies regarding the role of FMRP in regulating protein synthesis in brain function and development in recent years. That is why our paper is highly cited.

The Fmr1 gene encoding the fragile X protein is identified by positional cloning. Therefore, although the complete function of FMRP remains largely unknown, FMRP had been shown to bind RNA and polyribosomes in several reports including our own. This paper demonstrated that purified FMRP can bind to RNA in vitro, which is essential for FMRP to repress translation of its bound mRNA. Obviously, this is an important key in understanding the functional significance of the biochemical interactions of FMRP with various molecules. Furthermore, considering the fact that protein synthesis is a critical control for synaptic activity and the absence of FMRP results in dendritic spine abnormalities, understanding how FMRP may control translation provides important insights in elucidating synaptic plasticity in a broader terminology.

Fragile X syndrome is the most common cause of genetically inherited mental impairment, affecting 1 in 4,000 males and 1 in 8,000 females worldwide. The lack of the fragile X protein (named FMRP) is solely responsible for the fragile X clinical phenotype. However, how FMRP functions to maintain normal brain function remains unknown. Our paper demonstrated that FMRP can bind its messenger RNA partners, the templates for producing functional proteins, and inhibit protein synthesis from these RNAs. This observation provides an important clue regarding how FMRP may control the normal function of brain neurons, and suggests that misregulated protein production may be the cause for fragile X mental retardation.

The unknown function of FMRP deeply intrigued me while I was a postdoctoral fellow in Dr. Steve Warren’s lab. We were the first group that identified the association of FMRP with translating polyribosomes on the mRNA as a messenger ribonucleoprotein (Feng et al., Mol. Cell, 1997). Therefore, directly testing whether and how FMRP may influence translation was a logical approach once I set up my own lab. In 1997, the Emory Fragile X Program was funded by the NIH. The combined efforts from our lab, the Warren lab, and the Wilkinson lab produced all the reagents needed for the experimental system, and the intensive discussion among the program members was the driving force behind the success of this study.