Identification and characterization of Orb protein interactors involved in <i>orb</i> autoregulation

2004 2004

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Abstract (summary)

Spatiotemporal regulation of eukaryotic mRNA translation depends upon the coordination of asymmetric mRNA localization and translational regulation within specific subcellular compartments. The early development of many metazoans is driven by localized mRNAs whose translation in the developing egg and embryo underlies a variety of developmental decisions. In the Drosophila ovary, the determination of cell fate and the establishment of polarity depends upon pathways that localize mRNAs within the developing egg chamber and control their on site translation. CPEB/Orb proteins comprise a family of evolutionarily conserved RNA-binding proteins involved in RNA localization and required to activate the translation of localized mRNAs. Moreover, critical to carrying out its functions, Orb protein autoregulates its own synthesis by binding to orb mRNA and activating its translation. In the studies reported here, we have sought to identify proteins that associate with Orb protein and modulate orb autoregulation. Here we show that the Drosophila Fragile-X Mental Retardation (dFMR1) protein (whose human orthologue underlies the etiology of the Fragile-X syndrome) associates with Orb as part of a mRNP complex that controls the localized translation of mRNAs in the developing oocyte. Misexpression of Orb mRNA targets in absence of dfmr1 function indicates that dFMR1 negatively regulates Orb-mediated translational activation. In addition, dFMR1 regulates the distribution of CPEB/Orb protein in developing egg chambers by negatively regulating orb mRNA translation. Here, we also show that Rasputin, the Drosophila homologue of Ras-GAP SH3 Binding Protein (G3BP), is another component of the Orb mRNP complex. G3BP is a multifunctional protein overexpressed in several human tumors and believed to function as a link between Ras signaling and RNA metabolism. Genetic and biochemical analyses indicate that Rasputin associates with Orb and dFMR1 at the oocyte cortex and positively regulates orb autoregulation. Our results suggest a mechanism by which Fragile-X proteins may regulate localized translation in the nervous system and indicate that Rasputin may function as a link between Ras signaling and translational regulation.

Indexing (details)

Molecular biology;
Cellular biology;
0307: Molecular biology
0379: Cellular biology
0571: Pathology
Identifier / keyword
Health and environmental sciences; Biological sciences; Autoregulation; CPEB/Orb; Fragile X syndrome; Orb
Identification and characterization of Orb protein interactors involved in <i>orb</i> autoregulation
Costa, Alexandre
Number of pages
Publication year
Degree date
School code
DAI-B 65/09, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
9780496065752, 0496065750
Schedl, Paul
Princeton University
University location
United States -- New Jersey
Source type
Dissertations & Theses
Document type
Dissertation/thesis number
ProQuest document ID
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
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