ASCB 2013 PressBook - page 8

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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9
News from
The American Society
for Cell Biology
53rd Annual Meeting
New Orleans, LA
December 14–18, 2013
An old neuron’s guide to regeneration
EMBARGOED
FOR RELEASE
10:00 am, U.S. Central Time
Tuesday, December 17, 2013
Suppressing the
microtubule-cutting
enzyme, fidgetin,
allows injured adult
nerves to regrow
W
e talk about “hard
wiring” the brain
but our central
nervous system is a work
in progress. From the first
neuron through child-
hood and adolescence, the
neuronal network grows
in complexity and size but
also prunes out unneeded
connections using mole-
cules like the recently characterized enzyme,
fidgetin, which makes strategic cuts in the
microtubule scaffolding that holds up the
cell’s cytoskeleton and supports these con-
nections. The ability of nerves to grow and
prune diminishes as we mature until our
adult neurons have mostly lost the power
to reshape themselves. This is good for the
hard wiring of the nervous system but a
bitter pill when adult nerves are badly
injured or severed. They will not regenerate.
If researchers could learn to manipulate
anti-growth controls in damaged adult
neurons, they might be able to coax old
nerves into repairing broken connections.
Peter Baas, Lanfranco Leo, and col-
leagues at Drexel University have teamed
with David Sharp at the
Albert Einstein College of
Medicine (who first identi-
fied fidgetin as a microtu-
bule cutter) to explore the
enzyme’s role in neurons.
They believe that fidgetin
prevents nerves from grow-
ing out of control during
development while acting as
a brake on unwanted nerve
growth in adults. By block-
ing fidgetin in the injured
nerves of adult rats using a
novel nanoparticle technol-
ogy, Leo
et al.
now report
that they were able to restart
growth, a finding with po-
tential implications for all
kinds of nerve injury, includ-
ing the most difficult chal-
lenge of all, spinal cord injury. This builds on
other work from David Sharp’s lab showing
that inhibiting fidgetin might help the heal-
ing of wounds such as skin after burns and
the heart after a coronary.
The enzyme comes by its name
honestly. Fidgetin is the protein product of
the fidgetin gene, which was first identified
from a mutant strain of “fidget” mice, and
named for their fidgety behavior. To block
fidgetin’s actions in adult rat neurons, Leo
et al.
used a novel approach for making the
fidgetin protein disappear. They used tiny
nanoparticles, developed by Joel and Adam
Friedman at Albert Einstein, infused with
siRNA (small interfering RNA) to bind the
messenger RNA transcribed from the fidge-
tin gene that was on its way to be translated
by the cell into the microtubule-cutting
fidgetin enzyme. The siRNA binding causes
the mRNA to be tagged for
destruction. Thus fidgetin
is never translated.
“Depleting novel
microtubule-related
proteins represents a
new and proprietary
approach,” according to
the researchers, who have
formed a biotech com-
pany, MicroCures Inc.,
to commercialize their
approach. Among its uses,
they say, would be “tissue
regeneration and repair in
a wide range of therapeu-
tic contexts including:
spinal cord injury,
myocardial infarction,
and acute and chronic
cutaneous wounds.”
This work was funded in part by grants from the
Craig H. Neilsen Foundation and the Department
of Defense to the Baas and Sharp laboratories.
Contact
Peter W. Baas
Department of Neurobiology and
Anatomy, Drexel University
College of Medicine
2900 Queen Lane
Philadelphia, PA 19129
(215) 880 4226
David J. Sharp
Department of Physiology and
Biophysics, Albert Einstein
College of Medicine
1300 Morris Park Avenue
Bronx, NY 10461
Chief Science Officer
MicroCures Inc.
Santa Cruz, CA 95060
Authors Present
Tuesday, December 17, 2013
12:00 PM–1:30 PM
Neuronal Cytoskeleton II
Presentation 1898
Poster B323
Exhibit Halls B–D
Fidgetin restrains axonal growth
during neuronal maturation by a
microtubule-based mechanism
and provides a means for thera-
peutically enhancing regeneration
of injured adult axons
Lanfranco Leo
1
, Timothy O. Austin
1
,
Andrew Matamoros
1
, Wenqian
Yu
1
, Daniel R. Marenda
2
, David J.
Sharp
3,4
, Peter W. Baas
1,4
1
Department of Neurobiology and
Anatomy, Drexel University College
of Medicine, Philadelphia, PA
2
Department of Biology, Drexel
University, Philadelphia, PA
3
Department of Physiology and
Biophysics, Albert Einstein College
of Medicine, New York, NY
4
Co-senior authors
Shown in this figure are adult
rat neurons in culture growing
on a healthy substrate (dark
red) toward a substrate coated
with injury-related molecules
(light red). Panel A shows
fidgetin inhibition, with the
axon crossing onto the inhibi-
tory substrate, growing longer,
and showing higher levels of
microtubules, as represented by
the fluorescent green color of
the axon. Panel B shows what
normally happens, with less
axon growth, no crossing onto
the inhibitory substrate, and
lower levels of microtubules.
Quantitative data are shown in
panels C and D.
Shown in this schematic is the thinking
of the scientific team on how depleting
fidgetin enables microtubules to grow
in mass, thus pushing the axon to grow
into the normally inhibitory region.
I,II,1,2,3,4,5,6,7 9,10,11,12,13
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