Activity-dependent
plasticity
of
the
axon
initial
segment
(AIS)
endows
neurons
with
ability
to
adapt
action
potential
output
changes
in
network
activity.
Action
initiation
at
AIS
highly
depends
on
clustering
voltage-gated
sodium
channels,
but
molecular
mechanisms
regulating
their
remain
largely
unknown.
Here,
we
developed
genetic
tools
label
endogenous
channels
and
scaffolding
protein,
reveal
nanoscale
organization
longitudinally
image
hippocampal
slices
primary
cultures.
We
find
that
N
-methyl-
d
-aspartate
receptor
activation
causes
both
long-term
synaptic
depression
rapid
internalization
within
minutes.
The
clathrin-mediated
endocytosis
distal
increases
threshold
for
generation.
These
data
a
fundamental
mechanism
activity-dependent
reorganization
suggests
intrinsic
excitability
shares
conserved
features
plasticity.
From
trafficking
to
maintenance
Neurons
are
remarkably
polarized
in
that
proteins
made
the
cytosol
often
need
travel
many
tens
or
hundreds
of
cell
body
lengths
along
axons
their
sites
action
synapse.
Axonal
transport
these
components
is
driven
by
molecular
motors
axonal
microtubules.
Guedes-Dias
and
Holzbaur
review
biology
highlight
roles
this
fundamental
process
plays
organismal
health.
Science
,
issue
p.
eaaw9997
Nature,
Год журнала:
2024,
Номер
626(8001), С. 1116 - 1124
Опубликована: Фев. 14, 2024
Abstract
Transposable
elements
(TEs)
are
a
major
constituent
of
human
genes,
occupying
approximately
half
the
intronic
space.
During
pre-messenger
RNA
synthesis,
TEs
transcribed
along
with
their
host
genes
but
rarely
contribute
to
final
mRNA
product
because
they
spliced
out
together
intron
and
rapidly
degraded.
Paradoxically,
an
abundant
source
RNA-processing
signals
through
which
can
create
new
introns
1
,
also
functional
2
or
non-functional
chimeric
transcripts
3
.
The
rarity
these
events
implies
existence
resilient
splicing
code
that
is
able
suppress
TE
exonization
without
compromising
pre-mRNA
processing.
Here
we
show
SAFB
proteins
protect
genome
integrity
by
preventing
retrotransposition
L1
while
maintaining
integrity,
via
prevention
previously
integrated
TEs.
This
unique
dual
role
possible
L1’s
conserved
adenosine-rich
coding
sequences
bound
proteins.
suppressive
activity
extends
tissue-specific,
giant
protein-coding
cassette
exons,
nested
Tigger
DNA
transposons.
Moreover,
suppresses
LTR/ERV
in
species
still
active,
such
as
mice
flies.
A
significant
subset
suppressed
somatic
cells
activated
testis,
coinciding
low
expression
postmeiotic
spermatids.
Reminiscent
division
labour
between
innate
adaptive
immune
systems
fight
external
pathogens,
our
results
uncover
RNA-based,
pattern-guided,
non-adaptive
defence
system
against
soma,
complementing
Piwi-interacting
pathway
germline.
Nature Communications,
Год журнала:
2019,
Номер
10(1)
Опубликована: Дек. 20, 2019
Recent
super-resolution
microscopy
studies
have
unveiled
a
periodic
scaffold
of
actin
rings
regularly
spaced
by
spectrins
under
the
plasma
membrane
axons.
However,
ultrastructural
details
are
unknown,
limiting
molecular
and
mechanistic
understanding
these
enigmatic
structures.
Here,
we
combine
platinum-replica
electron
optical
to
investigate
cortical
cytoskeleton
axons
at
level.
Immunogold
labeling
correlative
super-resolution/electron
allow
us
unambiguously
resolve
as
braids
made
two
long,
intertwined
filaments
connected
dense
mesh
aligned
spectrins.
This
arrangement
contrasts
with
currently
assumed
model
short,
capped
filaments.
Along
proximal
axon,
resolved
presence
phospho-myosin
light
chain
connection
microtubules
via
ankyrin
G.
We
propose
that
braided
explain
observed
stability
actin-spectrin
ultimately
participate
in
preserving
axon
integrity.
Current Opinion in Neurobiology,
Год журнала:
2019,
Номер
57, С. 39 - 45
Опубликована: Фев. 10, 2019
Neurons
are
exquisitely
polarized
cells
whose
structure
and
function
relies
on
microtubules.
Microtubules
in
signal-receiving
dendrites
signal-sending
axons
differ
their
organization
microtubule-associated
proteins.
These
differences,
coupled
with
microtubule
post-translational
modifications,
combine
to
locally
regulate
intracellular
transport,
morphology,
function.
Recent
discoveries
provide
new
insight
into
the
regulation
of
non-centrosomal
arrays
neurons,
relationship
between
acetylation
mechanosensation,
spatial
patterning
microtubules
that
regulates
motor
activity
cargo
delivery
dendrites.
Together,
these
studies
bring
us
closer
understanding
how
is
tuned
match
specialized
tasks
associated
signal
reception
transmission.
Nature Communications,
Год журнала:
2020,
Номер
11(1)
Опубликована: Янв. 3, 2020
Axon
initial
segments
(AISs)
generate
action
potentials
and
regulate
the
polarized
distribution
of
proteins,
lipids,
organelles
in
neurons.
While
mechanisms
AIS
Na+
K+
channel
clustering
are
understood,
molecular
that
stabilize
control
neuronal
polarity
remain
obscure.
Here,
we
use
proximity
biotinylation
mass
spectrometry
to
identify
proteome.
We
target
biotin-ligase
BirA*
by
generating
fusion
proteins
with
NF186,
Ndel1,
Trim46;
these
chimeras
map
organization
intracellular
membrane,
cytosolic,
microtubule
compartments.
Our
experiments
reveal
a
diverse
set
biotinylated
not
previously
reported
at
AIS.
show
many
located
AIS,
interact
known
their
loss
disrupts
structure
function.
results
provide
conceptual
insights
resource
for
organization,
stability,
trafficking
Nature Communications,
Год журнала:
2021,
Номер
12(1)
Опубликована: Янв. 4, 2021
Abstract
The
axon
initial
segment
(AIS)
is
a
critical
microdomain
for
action
potential
initiation
and
implicated
in
the
regulation
of
neuronal
excitability
during
activity-dependent
plasticity.
While
structural
AIS
plasticity
has
been
suggested
to
fine-tune
activity
when
network
states
change,
whether
it
acts
vivo
as
homeostatic
regulatory
mechanism
behaviorally
relevant
contexts
remains
poorly
understood.
Using
mouse
whisker-to-barrel
pathway
model
system
combination
with
immunofluorescence,
confocal
analysis
electrophysiological
recordings,
we
observed
bidirectional
cortical
pyramidal
neurons.
Furthermore,
find
that
functional
remodeling
occurs
distinct
temporal
domains:
Long-term
sensory
deprivation
elicits
an
length
increase,
accompanied
increase
excitability,
while
enrichment
results
rapid
shortening,
by
decrease
generation.
Our
findings
highlight
central
role
input-output
relations.
