ASCB 2013 PressBook - page 7

T H E A M E R I C A N S O C I E T Y F O R C E L L B I O L O G Y
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8
News from
The American Society
for Cell Biology
53rd Annual Meeting
New Orleans, LA
December 14–18, 2013
A gene called Sunday Driver steers researchers
to answers for congenital muscle disease
EMBARGOED
FOR RELEASE
10:00 am, U.S. Central Time
Monday, December 16, 2013
Contact
Mary K. Baylies
Sloan-Kettering Institute
1275 York Ave, Box 310
New York, NY 10065
(212) 639-5888
Victoria Schulman
Authors Present
Monday, December 16, 2013
1:30 PM−3:00 PM
Tissue Development and
Morphogenesis II
Presentation 1431
Poster B1164
Exhibit Halls B–D
Sunday Driver (Syd) regulates
myonuclear positioning and
muscle function
V.K. Schulman
1,2
, E.S. Folker
2
,
M.K. Baylies
2
1
Department of Cell and Devel-
opmental Biology, Weill Cornell
Graduate School of Medical
Sciences, New York, NY
2
Program in Developmental
Biology, Sloan-Kettering
Institute, New York, NY
Funding for Victoria K. Schulman:
Award Number T32HD060600 from
the Eunice Kennedy Shriver National
Institute of Child Health and Human
Development, National Institutes of
Health; Bethesda, MD.
Funding for Mary K. Baylies: Award
Number GM078318 from the
National Institute of General Medi-
cal Sciences, National Institutes of
Health; Bethesda, MD. Research
Grant from the Muscular Dystrophy
Association; Tucson, AZ.
Mutating a fly gene and rescuing
its function with a mammalian
equivalent reveals how mispositioned
nuclei in skeletal muscle cells
are a possible cause of inherited
myopathies
A
whimsically named fly gene, Sunday
Driver, a.k.a.
syd,
and its mammalian
analog, JIP3, seem to be in the driver’s
seat when it comes to parking the multiple
nuclei of a skeletal muscle cell in their cor-
rect places, say researchers at the Sloan-
Kettering Institute (SKI). Getting that wrong
and having mispositioned nuclei is a classic
diagnostic sign of human congenital myopa-
thies, a string of inherited muscle diseases
such as Emery-Dreifuss muscular dystrophy
(EDMD). When Victoria Schulman in the SKI
lab of Mary Baylies mutated the
syd
gene in
the
Drosophila melanogaster
model, both
the embryonic and larval muscle tissue in
flies showed unevenly spaced and clustered
nuclei. The hatched larvae with defective
Syd protein were hobbled, crawling much
more slowly than their healthy counterparts.
Furthermore, flies with defective Syd protein
moved much more slowly than their healthy
counterparts. Adding mammalian JIP3
protein to the
syd
gene mutant flies rescued
nuclear spacing and locomotive ability.
Looking at flies to investigate the cell
biology of human muscle diseases may seem
like the long way around, but Schulman
and Baylies thought they could get clearer
answers in the flexible fly model than in
traditional human muscle cell cultures. Basic
answers are definitely needed. Congenital
myopathies account for one-tenth of all neu-
romuscular disorders, causing deterioration
of skeletal muscle and eventually death.
Studying congenital myopathies such
as EDMD poses special challenges for cell
biologists. Unlike typical cells, which have a
single nucleus located in the center of each
cell, muscles are composed of long multi-
nucleated cells with the nuclei strung out like
seeds in a bean pod. That’s because muscle
cells arise from the fusion of numerous
myoblasts, the building blocks of muscles.
Post-fusion, the many nuclei within the new
cell spread out to maximize internuclear
distance and usually move to the cell
periphery to avoid interfering with muscle
contraction. Skeletal muscle cells with
unevenly spaced nuclei, or nuclei parked
in the wrong spot, are telltale in tissue
biopsies of patients with suspected
inherited muscle disease such as EDMD
(1/100,000 births) and centronuclear
myopathy (1/50,000 births). And yet no one
is certain whether out-of-position nuclei are
a cause or consequence of muscle disease.
Schulman and Baylies believed that
the fruit fly was an ideal organism for these
studies because its life cycle begins with an
embryonic stage that would reveal critical
details about initial muscle formation.
Embryos then hatch into larvae that must
crawl toward food, providing a measure to
assay muscle function.
Using the fruit fly model system,
Schulman and Baylies identified three types
of proteins required for proper myonuclear
positioning: 1) cytoskeletal filaments
known as microtubules, which serve as
“tracks” or cellular “roadways,” 2) the motor
proteins kinesin and dynein, which travel
along these tracks, and 3) motor protein
regulators such as Ensconsin and Sunday
Driver (Syd). Mechanistically, Syd works as
a control switch to activate one motor at a
time, coordinating efforts to pull and move
muscle cell nuclei into proper position.
“Collectively, we implicate
syd
as a
necessary regulator of nuclear positioning
in muscle tissue, and show that misposi-
tioned nuclei are a possible cause, not a
consequence, of muscle disease,” write
Schulman and Baylies.
Drosophila larval muscles, stained for sarcomeres
(contractile units of muscle) in red and nuclei in white.
A) Side view of Wild-type muscle, displaying the
peripheral location of nuclei in muscle cells, outside the
boundaries of the sarcomeres. B) Top view of muscles,
highlighting the presence of mispositioned nuclei in syd
mutants. However, note the restored spacing of nuclei in
Drosophila syd mutant muscles expressing mammalian
JIP3 protein.
I,II,1,2,3,4,5,6 8,9,10,11,12,13
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