Current Research Projects in the Lab:
Diminished Fragile X mental retardation protein (FMRP) activity in humans causes Fragile
X Syndrome (FXS), the most common form of heritable mental retardation (O'Donnell and
Warren, 2002). Although FMRP has been shown to be an RNA-binding protein that represses
mRNA translation in vitro and in vivo (Laggerbauer et al., 2001; Li et al., 2001), its
precise mechanism of action is unknown. In fact, some evidence suggests that FMRP might
also function as a translational activator of specific transcripts in vivo (Brown et
al., 2001; Miyashiro et al., 2003; Monzo et al., 2006; Todd et al., 2003).
Mechanisms of mRNA metabolism in cellular morphogenesis.
Figure 5. Misexpression of TRAL protein is observed in fixed cellularizing dfmr1 embryos by immunofluorescence. Scale bar represents 10 μm. From Monzo, et al., 2006.
We identified a previously unknown requirement for dFMRP, the single Drosophila ortholog of human FMRP, in cleavage furrow formation and have demonstrated that it functions within cytoplasmic ribonucleoprotein (RNP) bodies during the MZT (Monzo et al., 2006). Through a combination of biochemistry and immunofluorescence analysis we have learned that dFMRP colocalizes with the cytoplasmic RNP body components Trailer Hitch (TRAL)(Wilhelm et al., 2005) and Maternal Expression at 31B (Nakamura et al., 2001) in cleavage stage embryos, but it does not complex with either protein. Rather dFMRP associates with tral mRNA and is required for the expression and localization of TRAL protein (Figure 5)(Monzo et al., 2006).
This discovery is significant because tral mRNA is the first in vivo FMRP target identified that encodes another translation factor, raising the possibility that the cognitive symptoms of FXS could involve FMRP-dependent translational regulation of direct and indirect FMRP target mRNAs. Based on these observations we have initiated quantitative proteomic screens to identify in vivo mRNA targets of dFMRP-dependent translational regulation (Figure 6) and protein binding partners of dFMRP required for its function. These studies should provide valuable insights into the etiology of FXS and the molecular and cellular mechanisms of synaptic plasticity and cleavage furrow formation.