David R. Morris, PhD
Principal Investigator

David Brackett, PhD
Postdoctoral Fellow

University of Washington

While we commonly discuss the fragile X protein FMRP as if it were a single protein, actually 12 different versions of FMRP have been found in mouse brain cells. Alternative splicing of the FMR1 gene results in protein isoforms with different sizes and physical properties. How function varies in these isoforms is not known.

This team aims to understand the variation in distribution and function of FMRP isoforms. They seek to identify isoforms of FMRP in mouse brain, and define the expression pattern of these versions of the protein. This information, along with the reagents generated by this project, will be enormously valuable to the Fragile X research field.

by David Morris, PhD, 1/2007

The Fragile X Mental Retardation Protein (FMRP) contains a number of characterized functional domains that govern its movement between the nucleus and cytoplasm, its association with target mRNA molecules thought to be important for proper brain maturation, and its regulation by extracellular signals through phosphorylation and methylation. Multiple forms of FMRP, containing different functional domains, are all generated from the same gene by alternative processing of the mRNA. Our research focuses on analyzing the occurrence and functions of these FMR1 mRNA isoforms that encode proteins with varying physiological functions.

Work during our first year of FRAXA support demonstrated that 12 different FMR1 transcript isoforms are associated with polyribosomes in mouse brain, thus showing for the first time that all these transcripts are actively translated into protein. As well, our data reveal that these Fmr1 mRNA species are present at widely varying levels in two tissues affected by Fragile X syndrome, the brain and testes.

The Fmr1 transcripts that encode non-phosphorylated forms of FMRP are over-represented in the olfactory bulb of the adult mouse brain, a location where abundant neurogenesis takes place. This observation led us to hypothesize that these forms of FMRP, which are insensitive to signaling via phosphorylation, may play roles specific to stem cells. Experiments with replicating and differentiating neural stem cells in culture support this concept and we are currently investigating the expression of the individual isoforms through various stages of pre-natal and post-natal mouse brain development. We anticipate that these experiments will inform new and more specific hypotheses as to roles of the FMR1 isoforms in brain development and maturation.