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|Title:||MNB AND HIP-1: INTERACTION OF DOWN SYNDROME AND HUNTINGTON DISEASE GENES IN DROSOPHILA|
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|Authors/Affiliations:||1 Jillian MacDonald*; 1 Brian Staveley; |
1 Memorial University of Newfoundland, St. John's, NL, Canada
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|Content:||Objectives: Our goal is to discover in vivo genetic interactions between mnb and hip-1 during neurogenesis and growth using the Drosophila model system.|
Down syndrome (DS) is a neurogenerative disorder and the most frequent cause of human mental retardation. DS results from a total or partial triplication of chromosome 21 with one important candidate gene identified as Dyrk1A (dual-specificity YAK1-related kinase A). We have shown that minibrain (mnb), the Drosophila homologue of Dyrk1A, controls growth through modification of insulin receptor signaling (Rotchford and Staveley, unpublished).
Huntington disease (HD) is a dominantly-inherited neurodegenerative disorder caused by a polyglutamine expansion in the amino terminus of the huntingtin (htt) protein. Hip-1 (Huntingtin-interacting protein-1) interacts with this region of htt. Our lab has characterized the role of two versions of the Hip-1 protein, a longer version containing a lipid binding domain, and a shorter version lacking the lipid binding domain, Hip-1ANTH, in Drosophila neurogenesis (Moores, Roy, Nicholson and Staveley, unpublished).
Recently, biochemical interactions between Hip-1 and Dyrk1A in tissue culture have been reported (Kang et al., 2005). Our study aims to identify and characterize interactions between the Drosophila homologue of Dyrk1A (mnb) and Hip-1 through biometric analysis of the development of ommatidia and mechanosensory bristles in Drosophila.
Materials and Methods: As Drosophila provide an ideal model to study both growth and neurogenesis, directed expression studies during development were performed using the UAS-Gal4 system. Combinations of mnb mutants/transgenics and both versions of hip-1 were generated. Biometric analysis of eyes and dorsal notums of flies were conducted via scanning electron microscope (SEM) imaging and ImageJ software analysis.
Results: Bristle density in the dorsal notum is significantly greater in females overexpressing mnb. When expressed in the eye, hip-1ANTH results in significantly reduced ommatidial area as compared to controls. In addition, directed expression of mnb leads to significantly greater bristle number in the eye. Under standard conditions, no significant difference in ommatidia number was observed as the result of the expression of either mnb or hip-1. However, the expression of foxo sensitizes eye development to subtle changes in growth (Kramer et al., 2003), and flies overexpressing mnb and hip-1 along with foxo result in significantly lower numbers of ommatidia. Reflecting the dichotomy of hip-1 and hip-1ANTH influence upon neurogenesis (Moores et al., unpublished), mnb and hip-1 have less bristles and hip-1ANTH have significantly more bristles develop in the eye when compared to controls.
Conclusions: This study suggests that mnb and hip-1 interact during development and show a subtle, yet potentially important biological link between genes involved in very different human neurological disorders.
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