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Poster Full Abstracts - Drosophila Models of Human Diseases
Poster board number is above title. The first author is the presenter
239
occurs first and prevents Dpp signaling leading to wing phenotypes. It is likely that this same mechanism explains the morphological defects of Anderson-
Tawil Syndrome.
395B
Interactions between the HuD homolog
fne
and the
dNab2
polyadenosine RNA binding factor in a fly model of human intellectual disability.
Rick
Stephen Bienkowski
1
, Callie Wigington
2
, Anita Corbett
2
, Ken Moberg
1
. 1) Cell Biology, Emory University, Atlanta, GA; 2) Biochemistry, Emory
University, Atlanta, GA.
Intellectual disability (ID), previously referred to as mental retardation, is a broad term for a collection of diseases that are characterized by limited
intellectual capacities and major constraints in adaptive behavior. We have recently found that inactivating mutations in the human gene encoding ZC3H14,
a polyadenosine RNA binding protein, cause autosomal recessive non-syndromic form of ID (NS-ARID). We have created a
Drosophila melanogaster
model of this disease by removing the orthologous gene,
dNab2
(aka CG5720), and these
dNab2
mutant flies recapitulate key aspects of the human
phenotype, including impaired neural function (see Pak et al, PNAS, 2011). Moreover in recent work we have also found that the form of ZC3H14 missing
in human NS-ARID patients can functionally substitute for dNab2 in the fly nervous system, indicating that ZC3H14 is a true functional ortholog of dNab2.
Our goal in future work is to understand the role of dNab2/ZC3H14 proteins in neurodevelopment and function. A key step in achieving this goal is
identifying mRNAs targeted by dNab2 in fly neurons. In preliminary work, we have used siRNA knockdown in human cells to identify mRNAs regulated by
ZC3H14 and by a second RNA binding protein, the human antigen-R (HuR) protein, which is a member of the Elav protein family and has strong affinity for
adenylate and uridylate rich elements (AREs). Preliminary evidence from these microarray experiments suggests that ZC3H14 and HuR may regulate a
common set of transcripts. In parallel, we have uncovered evidence of genetic interaction between dNab2 and the HuR homolog found in neurons (
fne
). In
light of these data, we have undertaken efforts to generate alleles of
fne
and other genes we believe act with dNab2 to control neurodevelopment and
function. We are also analyzing physical and functional interactions between these proteins in a cultured S2 cells and in cultured primary brain neurons.
396C
Modeling Degenerative Disc Disease in Drosophila melanogaster.
Megan C. Donegan, Joseph A. Chiaro, Hemlata Mistry. Department of Biology,
Widener University, Chester, PA.
Chronic back pain, associated with disorders of the muscles and vertebrae of the spine, is of great medical importance and results in annual societal losses
of over $90 billion. Degenerative disc disease (DDD) is a leading cause of disability in middle age. DDD arises when the integrity of the intervertebral disc
is compromised. The start of degeneration is not entirely environmental, since DDD can arise in juvenile adults. Studying the genetic basis of disc
degeneration is an emerging field. We are investigating changes that occur in gene expression following trauma to the ventral nerve cord in late-stage
Drosophila embryos. Although Drosophila is an invertebrate, our investigations are likely to be meaningful because a large proportion of human disease
genes have a homologous Drosophila counterpart. Furthermore, gene regulatory pathways that control patterning and cell fate decisions during the formation
of the nerve cord are conserved between humans and flies. We expect that similar changes in gene expression will occur in response to injury in both
organisms. We are using microarray analysis to detect changes in gene expression between wounded and control embryos. We are investigating candidate
genes of interest further via real time quantitative PCR. Understanding this genetic basis is crucial to identifying individuals at risk for degeneration,
identifying potential genes for therapy, and understanding the contributions of various genes to DDD onset and progression.
397A
The mechanism of nuclei positioning during muscle development in Drosophila.
Hadas Tamir, Yaxun V. Yu, Michael Welte, Talila Volk. Molecular
Genetics, Weizmann Institute, Rehovot, Israel.
Dynamic distribution of cellular organelles during muscle development is of crucial importance for myotube migration, attachment, and function. KASH
domain family members contribute to organelles dynamic localization in the cytoplasm. In this study we aimed to analyze the contribution of the two
Drosophila KASH proteins, Klarsicht (Klar) and MSP-300 to nuclei rearrangement during muscle development. We find that in embryonic myotubes, Klar
promotes nuclei migration to the plus-ends of microtubules, adjacent to the myotendinous junction. Subsequent muscle sarcomerization is then associated
with a significant organelles rearrangement. At this stage, MSP-300 promotes nuclei and mitochondria anchoring to the Z-discs, whereas Klar is driving
nuclei even spacing within the muscle cytoplasm. We present evidences suggesting that the two Drosophila KASH proteins are essential for proper muscle
development at key developmental stages, by allowing nuclei movement in a Klar-dependent manner, and nuclei anchoring to the Z-discs by a MSP-300-
dependent mechanism. In conclusion, our results provide a mechanistic explanation for the process of nuclei and mitochondria positioning during muscle
development. Since all these proteins are well conserved throughout evolution, this mechanism is highly relevant to vertebrate muscle development.
398B
A Drosophila Model of Friedreich's Ataxia and Autophagic Heart Disease.
Luan Wang. Inst Environmental Hlth Sci, Wayne State Univ, Detroit, MI.
Friedreich’s Ataxia (FRDA) is one of the most prevalent heritable neurodegenerative diseases in the United States. It is caused by the mutation of a
mitochondria iron chaperone gene Frataxin . The mutation significantly reduces the frataxin protein level and renders the patients with muscle weakness,
degeneration of neural cells, and heart disorder. But the details of the pathogenesis is still unclear and the disease is currently untreatable. Here we developed
a Drosophila model for FRDA by reducing the frataxin level in vivo through UAS-Gal4 system, which could decrease the frataxin levels in specific organs
such as the heart (tinman), neurons (elav), or the whole body (actin and daG32). The impact of neurotoxicity will be measured by the locomotive assay and
the visualized heart assay. We discovered that under normal condition, the frataxin deficient flies, daG32-FhIR, shows no significant difference compared to
the wild type flies. But after the treatment of 50 mM Paraquat, a reactive oxygen species (ROS) reagent, for 72 hours, the locomotive activity of daG32-FhIR
are greatly decreased. At the same time, the longevity of the daG32-FhIR are also affected negatively. We also observed that the Tinman-FhIR flies, which is
a relatively weaker promoter, shows no difference in development comparing to the wild type flies. In contrast, the stronger promoter line, daG32-FhIR is
pupae lethal at 25 °C, and can normally develop at 18°C. This suggests that there is a threshold for frataxin level to maintain the normal function. Its
reduction above the threshold is not essential at normal environment. But when the frataxin level decreases below the threshold, or the flies are challenged
by the oxidative stress from ROS and locomotive activity will be affected. We also found that the phenotypes of the frataxin-deficient flies are very similar