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Poster Full Abstracts - Drosophila Models of Human Diseases
Poster board number is above title. The first author is the presenter
251
mutants, suggesting that
dtorsin
plays a novel role in dopamine metabolism as a positive-regulator of GTP cyclohydrolase protein. The locomotion defect
was rescued by cDNA for both
dtorsin
and human torsinA. Moreover, co-expression of wild type together with a human disease form of htorsinA (ΔE302)
cDNA showed locomotion defect. Thus this
dtorsin
mutant line will be valuable for elucidating the function of torsin protein and the human disease
mechanism.
443B
Rejuvenation of meiotic cohesion: a conserved mechanism to combat age related chromosome segregation errors?
Katherine A. Weng, Charlotte A.
Jeffreys, Sharon E. Bickel. Biological Sciences, Dartmouth College, Hanover, NH.
Chromosome segregation errors during female meiosis I are the leading cause of birth defects and miscarriages, and as women age, the risk of aneuploid
pregnancy increases exponentially. Accurate chromosome segregation in human oocytes requires that meiotic sister chromatid cohesion remain intact for
decades and work in model organisms indicates that deterioration of meiotic cohesion over time may be a major determinant of age related aneuploidy. We
are using Drosophila to investigate whether oocytes rely exclusively on cohesive linkages that are established during meiotic S phase or if maintenance of
meiotic cohesion is an active process that requires rejuvenation throughout the extended period of prophase I. Deco is the Drosophila homolog of the yeast
cohesion establishment factor, Eco1, which is required to establish cohesive linkages during S phase. To test the hypothesis that Deco is required for
maintenance of meiotic cohesion, we used a Gal4/UAS inducible approach to knock down Deco after meiotic S phase in the female germ-line. Using the
synaptonemal complex (SC) protein C(3)G as a cytological marker to monitor cohesion, we find that reduction of Deco after meiotic S phase causes
premature disassembly of the SC. In addition, Deco knockdown during mid-prophase results in increased levels of meiotic nondisjunction (NDJ). A genetic
assay that allows us to determine the recombinational history of missegregating chromosomes indicates that although chiasmata are formed, they are not
maintained when Deco is knocked down after meiotic S phase. Moreover, SC defects and increased NDJ also occur when cohesin subunits are knocked
down after meiotic cohesion is established during S phase. These data argue that turnover of chromatin-associated cohesin and rejuvenation of cohesive
linkages are required during meiotic prophase to stabilize chiasmata and ensure proper segregation of meiotic chromosomes. We propose that these activities
represent a critical mechanism that allows metazoan oocytes to counteract the deterioration of cohesion caused by aging.
444C
A new
Drosophila
model of Spinal Muscular Atrophy highlights the importance of non-snRNP related functions of Survival Motor Neuron in
disease pathology.
Kavita Praveen
1
, Ying Wen
2
, T.K. Rajendra
2
, A.Gregory Matera
1,2
. 1) Genetics and Molecular Biology, University of North Carolina,
Chapel Hill, NC; 2) Department of Biology, University of North Carolina, Chapel Hill, NC.
Spinal Muscular Atrophy (SMA) is a common neuromuscular disease that strikes one in 6,000-8,000 young children; most of whom die before the age of
two years. Greater than 95% of patients with SMA carry deletions or point mutations in the
survival motor neuron 1
(SMN1)
gene. The SMN protein is
essential for survival and has a well-characterized role in the biogenesis of small nuclear ribonucleoproteins (snRNPs), which are core components of the
spliceosome. Numerous additional functions have been put forth in the literature, however, no convincing link has been made between any putative SMN
function and the disease etiology. We have developed a
Drosophila
model system to study the consequences of SMN loss of function mutations. In order to
uncouple the housekeeping and tissue-specific functions of SMN, we have generated a series of transgenic flies that express human SMA patient-derived
point mutations that are conserved in the fly. The transgenes are expressed using the endogenous
Smn
promoter and are integrated at the same genomic
locus. Null mutants in
Smn
die as larvae, show significant motility defects, and have reduced levels of minor-class snRNAs, U4atac and U12. Surprisingly,
we find that transgenic expression of relatively low amounts of wild-type SMN fail to restore snRNA levels but can rescue both the locomotor defects and
lethality of the Smn null flies, producing fertile adults. Similarly, expression of an SMA point mutant construct,
Smn
T205I
, rescues the larval motility defects,
but the majority of these animals die as pupae with an snRNA profile identical to that of the wild-type transgenics. These data demonstrate that the reduction
in snRNA levels observed in
Smn
mutants is not a major contributor to lethality, and indicate that non-snRNP related functions of SMN play important roles
in SMA pathology.