Reduced activity of Fragile X mental retardation protein (FMRP) in brain neurons results in the most common form of heritable mental retardation in humans, Fragile X Syndrome (FXS). FMRP is a selective RNA-binding protein that is implicated in the translational regulation of specific mRNAs in neurons. Although very few direct targets of FMRP have been identified and verified in vivo, FXS is thought to result from the aberrant regulation of potentially hundreds of mRNAs causing defects in neuron morphology and synapse function. Identifying additional targets will be important for elucidating the mechanism of FMRP regulation as well as the etiology of FXS.
Drosophila melanogaster offers a unique and powerful system for studying the function of FMRP. Flies with loss of FMRP activity have neuronal and behavioral defects similar to those observed in humans with FXS. Importantly, FMRP regulates common target mRNAs in neurons in both mice and flies. Here, I will describe our discovery of a previously unknown requirement for Drosophila FMRP (dFMRP) during the cleavage stage of early embryonic development. First, we identified a requirement for dFMRP for proper cleavage furrow formation and found that dFMRP functions to regulate the expression of specific target mRNAs during the cleavage stage. Among these is trailer hitch (tral) mRNA, which encodes a translational regulator as well, and represents a new in vivo target of dFMRP translational regulation. In addition, I have identified twenty-eight proteins that change in expression in the absence of dFMRP using a comparative proteomics based screen for dFMRP targets. One of these is the Chaperonin containing tcp-1 complex (CCT), a previously unidentified target, which I found is itself also required for cleavage furrow formation. Finally, we have identified a new dFMRP protein-binding partner, Caprin, and found that together dFMRP and Caprin are required for the proper timing of the MBT. This set of work has led to a better understanding of the mechanism of dFMRP-dependent regulation of cellular morphogenesis in early embryos and has the potential to lead to a better understanding of the etiology of FXS. / text
| Identifer | oai:union.ndltd.org:UTEXAS/oai:repositories.lib.utexas.edu:2152/ETD-UT-2009-12-411 |
| Date | 20 August 2010 |
| Creators | Monzo, Kate Frances |
| Contributors | Sisson, John Charles, Macdonald, Paul M. |
| Source Sets | University of Texas |
| Language | English |
| Detected Language | English |
| Type | thesis |
| Format | application/pdf |
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