Basic HTML Version
Full Abstracts – DROSOPHILA MODELS OF HUMAN DISEASE
127
23
Cell-Specific MeCP2 expression changes Sleep Patterns and Aggressive Behavior in a Drosophila model of MeCP2 Spectrum Disorders.
Sarah J.
Certel, Tarun Gupta, David Hess-Homeier, Conor Jacobs, Brittany Felgate. Division of Biological Sciences, University of Montana, Missoula, MT.
Methyl-CpG-binding protein 2 (MeCP2) is expressed in nearly every cell in the human body and is one of the most dosage-sensitive genes involved in
neuron function. Due to the widespread expression of MeCP2, the complexities of human disorders associated with mutations in the MeCP2 gene including
Rett Syndrome and MeCP2 Duplication disorders are considerable. Key behavioral changes in patients can include increased aggression levels and
significant sleep disturbances. To determine whether neuronal or glial changes in MeCP2 expression cause the neurological dysfunction and alterations in
behavior, we expressed human MeCP2 in astrocytes and distinct subsets of amine neurons including dopamine and octopamine (OA) neurons. Our results
indicate there are quantifiable behavioral differences between astrocytic MeCP2-expression and OA neuron-MeCP2 expression both in sleep patterns, sleep
latency, and duration of sleep bouts. Specifically, expression of MeCP2 in astrocytes results in a significant reduction in the number of nighttime sleep bouts.
A slight increase in latency to sleep is also observed indicating nighttime sleep is both delayed and reduced. In contrast, daytime sleep is significantly
reduced in males expressing MeCP2 in OA neurons. Although activity levels are not reduced in MeCP2-expressing flies, male aggressive behavior is
significantly decreased as compared to control males. Fights between males expressing MeCP2 in octopamine neurons or astrocytes exhibit a decrease in
lunge number and an increase in latency to initiate aggression. Finally, we examined if the morphology of amine neurons is altered either non-cell-
autonomously or cell-autonomously by astrocytic vs. neuronal MeCP2 expression. Given the complexities of MeCP2 function, our results provide insight
into the distinct cell types, glial and neuronal, that mediate key behavioral changes tied to alterations in MeCP2 function. (NIH COBRE grant P20RR015583
to SJC).
24
Organotypic models for kidney disease:
Drosophila
gets kidney stones, too.
Julian A T Dow
1
, Pablo Cabrero
1
, Taku Hirata
2
, Michael Romero
2
. 1)
Institute of Molecular, Cell and Systems Biology, University of Glasgow, Glasgow, United Kingdom; 2) Physiology & Biomedical Engineering & O’Brien
Urology Research Center, Mayo Clinic, Rochester, MN 55905 USA.
Although there are homologs for over 70% of human genes in
Drosophila
, the best disease models are organotypic - that is, when the fly homolog is
expressed in the most appropriate tissue for the disease (1, 2). The Malpighian tubule provides an excellent model for renal function and disease (3).
Nephrolithiasis represents a major health burden, costing over $5B/ yr in the US alone. Insect Malpighian tubules in fact express two major classes of stone
(phosphate and urate) constitutively, and the rosy mutant exactly recapitulates the renal & metabolic phenotypes of human xanthinuria type I (4, 5). The
most common stones in humans are of calcium oxalate, with a complex etiology including a dietary component, and here we show that dietary oxalate
loading rapidly induces stones in
Drosophila
tubules (3, 7). Furthermore, stone formation in isolated tubules can be induced in minutes by addition of
oxalate, allowing the nucleation event to be monitored in situ for the first time (3). The utility of the model would be increased if specific genes could be
associated with stone formation. We have identified prestin, an SLC26A5/6 homolog with strong expression in the gut and tubules, as a key oxalate
transporter that mediates stone formation, as dsRNA-mediated knockdown of prestin in just tubule principal cells is sufficient to reduce the rate of stone
formation. Given the range of quantitative phenotypic readouts available in this tissue (7), it is clear that the Malpighian tubule offers an unusually good
model for human function and disease. 1.J. A. T. Dow, S. A. Davies, J. Insect Physiol. 52, 365 (2006). 2.V. R. Chintapalli et al. Nat. Genet. 39, 715 (2007).
3.J. A. T. Dow, M. F. Romero, Am J Physiol Renal Physiol 299, F1237 (2010). 4.J. Wang et al., Genome Biol. 5, R69 (2004). 5.M. A. Kamleh et al. FEBS
Lett. 582, 2916 (2008). 6.Y. H. Chen et al., Kidney Int. 80, 369 (2011). 7.J. A. T. Dow, S. A. Davies, Physiol. Reviews 83, 687 (2003).