bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Март 31, 2024
Abstract
Background
Branching
morphogenesis
orchestrates
organogenesis
in
many
tissues
including
kidney,
where
ureteric
bud
branching
determines
kidney
size
and
nephron
number.
Defects
result
congenital
renal
anomalies
which
manifest
as
deviations
size,
function,
number
thus
critically
compromising
the
lifelong
functional
capacity
established
during
development.
Advances
genetic
molecular
understanding
of
regulation
have
proved
insufficient
to
improve
prognosis
defects.
Thus,
we
addressed
mechanisms
regulating
three-dimensional
(3D)
epithelial
cell
morphology
shape
changes
novel
branch
initiation
uncover
contributions
cellular
mechanics
on
functions
tissue
organization
normal
branching-compromised
tips.
Methods
We
explored
behavior
at
all
scales
by
utilizing
a
combination
mouse
genetics
custom
machine-learning
segmentation
pipeline
MATLAB.
Ureteric
shapes
sizes
were
quantified
3D
wholemount
kidneys.
A
with
live
imaging
fluorescently
labelled
UB
cells,
traction
force
microscopy,
primary
cells
used
determine
how
basic
features
niche
biomechanics
contribute
complex
point
determination
process
that
aims
gaining
optimal
growth
density
limited
space.
Results
Machine
learning-based
tip
epithelia
identified
geometrical
round-to-elliptical
transformation
key
change
facilitating
shifts
direction
enable
propitious
complexity.
Cell
analyses
demonstrated
failure
condense
conformation.
Analysis
derived
disrupted
E-CADHERIN
PAXILLIN
mediated
adhesive
forces
defective
cytoskeletal
dynamics
detected
fluorescent
labelling
actin
cells.
Branching-compromised
showed
wrinkled
nuclear
alterations
MYH9-based
microtubule
organization,
suggest
stiff
disturbed
sensing
response
biomechanical
cues.
Conclusions
Our
results
indicate
within
epithelium
towards
composed
progenitors
must
dynamically
fluctuate
allow
complexity
arborization
new
formation.
The
data
collectively
propose
model
crowding
tandem
stretching
transforms
individual
into
elliptical
elongated
shapes.
This
creates
local
curvatures
drive
formation
ampulla-to-asymmetric
ampulla
transition
bud.
Frontiers in Cell and Developmental Biology,
Год журнала:
2023,
Номер
11
Опубликована: Дек. 6, 2023
Breast
cancer
is
characterized
by
physical
changes
that
occur
in
the
tumor
microenvironment
throughout
growth
and
metastasis
of
tumors.
Extracellular
matrix
stiffness
increases
as
tumors
develop
spread,
with
stiffer
environments
thought
to
correlate
poorer
disease
prognosis.
Changes
extracellular
other
characteristics
are
sensed
integrins
which
integrate
these
cues
intracellular
signaling,
resulting
modulation
proliferation
invasion.
However,
co-ordination
mechano-sensitive
signaling
functional
groups
cells
within
3-dimensional
remains
poorly
understood.
Here
we
provide
evidence
increasing
collagen
scaffolds
results
increased
activation
ERK1/2
YAP
human
breast
cell
spheroids.
We
also
show
acts
upstream
this
context.
further
demonstrate
YAP,
metalloproteinases
actomyosin
contractility
required
for
remodeling,
invasion
lower
scaffolds.
proteins
higher
gels
correlated
reduced
Our
data
collectively
induce
mechano-signaling
but
contrary
from
2-dimensional
studies,
not
sufficient
promote
pro-tumorigenic
effects
Candidate
cardiomyocyte
(CM)
mitogens
such
as
those
affecting
the
extracellular
signal–regulated
kinase
(ERK)
signaling
pathway
represent
potential
targets
for
functional
heart
regeneration.
We
explored
whether
activating
ERK
via
a
constitutively
active
mutant
of
B-raf
proto-oncogene
(BRAF),
BRAF-V600E
(caBRAF),
can
induce
proproliferative
effects
in
neonatal
rat
engineered
cardiac
tissues
(ECTs).
Sustained
CM-specific
caBRAF
expression
induced
chronic
activation,
substantial
tissue
growth,
deficit
sarcomeres
and
contractile
function,
stiffening,
all
which
persisted
at
least
4
weeks
culture.
caBRAF-expressing
CMs
ECTs
exhibited
broad
transcriptomic
changes,
shift
to
glycolytic
metabolism,
loss
connexin-43,
promigratory
phenotype.
Transient,
doxycycline-controlled
revealed
that
induction
CM
cycling
is
rapid
precedes
decline,
are
reversible
only
with
short-lived
activation.
Together,
direct
activation
BRAF
sufficient
modulate
phenotype,
offering
mechanistic
insights
into
roles
context
development
Nano Letters,
Год журнала:
2023,
Номер
23(17), С. 7950 - 7960
Опубликована: Июль 7, 2023
It
is
a
big
challenge
to
design
biomimetic
physical
microenvironment
with
greater
similarity
in
vivo
tissue
observe
real
cell
behaviors.
We
established
novel
culture
platform
based
on
patterned
equidistant
micropillars
stiff
and
soft
stiffnesses
mimic
the
changes
that
happened
transition
from
normal
osteoporotic
disease.
first
demonstrated
micropillar
substrate
decreased
osteocyte
synaptogenesis
through
synaptogyrin
1
this
decrease
was
accompanied
by
impairment
of
mechanoperception
cellular
cytoskeletal
rearrangement.
then
found
reduced
mainly
via
inactivation
Erk/MAPK
signaling.
finally
substrate-mediated
impacted
cell-to-cell
communication
matrix
mineralization
osteocytes.
Taken
together,
study
provides
evidence
mechanical
responses
are
much
more
similar
those
osteocytes
at
bone
level.
Proceedings of the National Academy of Sciences,
Год журнала:
2023,
Номер
120(32)
Опубликована: Авг. 1, 2023
Optogenetic
tools
respond
to
light
through
one
of
a
small
number
behaviors
including
allosteric
changes,
dimerization,
clustering,
or
membrane
translocation.
Here,
we
describe
new
class
optogenetic
actuator
that
simultaneously
clusters
and
translocates
the
plasma
in
response
blue
light.
We
demonstrate
dual
translocation
clustering
BcLOV4
photoreceptor
can
be
harnessed
for
novel
single-component
tools,
control
entire
family
epidermal
growth
factor
receptor
(ErbB1-4)
tyrosine
kinases.
further
find
are
mechanistically
linked.
Stronger
increased
magnitude
downstream
signaling,
sensitivity
by
~threefold-to-fourfold,
decreased
expression
levels
needed
strong
signal
activation.
Thus
light-induced
provides
strategy
generate
enhance
existing
ones.
EGFR-ERK
signaling
controls
cell
cycle
progression
during
development,
homeostasis,
and
disease.
While
EGF
ligand
mechanical
inputs
can
activate
signaling,
the
molecules
linking
force
to
this
axis
have
remained
mysterious.
We
previously
found
that
stretch
promotes
mitosis
via
stretch-activated
ion
channel
Piezo1
ERK
signaling.
Here,
we
show
provides
missing
link
between
signals
activation.
both
EGF-
Piezo1-dependent
activation
trigger
clathrin-mediated
EGFR
endocytosis
activation,
relies
on
canonical
tyrosine
autophosphorylation,
whereas
involves
Src-p38
kinase-dependent
serine
phosphorylation.
In
addition,
unlike
EGF,
ex
vivo
lung
slices
treated
with
agonist
promoted
re-entry
nuclear
ERK,
AP-1
(FOS
JUN),
YAP
accumulation,
typical
of
regenerative
malignant
Our
results
suggest
Piezo1,
Src,
p38
may
be
more
relevant
controlling
repair,
regeneration,
cancer
growth
than
kinase
suggesting
an
alternative
therapeutic
approach.
Journal of Biological Chemistry,
Год журнала:
2023,
Номер
299(10), С. 105224 - 105224
Опубликована: Сен. 9, 2023
Faced
with
the
remarkable
complexity
of
cellular
signaling
networks,
human
brain
naturally
turns
to
a
reductionist
approach
that
seeks
characterize
smaller
units,
commonly
known
as
pathways,
and
their
individual
components.
This
has
proven
essential
for
understanding
pleiotropic
physiological
processes
attributed
PI3K
well
consequences
disease-causing
aberrations
in
pathway
biochemical
molecular
discovery
resulted
identification
multiple
different
catalytic
regulatory
isoforms
PI3K,
biosynthetic
routes
key
lipid
products
second
messengers
PIP3
PI(3,4)P2,
effectors
such
AKT
downstream
substrates.
Receptor
tyrosine
kinases
(RTKs)
are
major
signaling
hubs
in
metazoans,
playing
crucial
roles
cell
proliferation,
migration,
and
differentiation.
However,
few
tools
available
to
measure
the
activity
of
a
specific
RTK
individual
living
cells.
Here,
we
present
pYtags,
modular
approach
for
monitoring
user-defined
by
live-cell
microscopy.
pYtags
consist
an
modified
with
activation
motif
that,
when
phosphorylated,
recruits
fluorescently
labeled
tandem
SH2
domain
high
specificity.
We
show
that
enable
on
seconds-to-minutes
time
scales
across
subcellular
multicellular
length
scales.
Using
pYtag
biosensor
epidermal
growth
factor
receptor
(EGFR),
quantitatively
characterize
how
dynamics
vary
identity
dose
activating
ligand.
orthogonal
can
be
used
monitor
EGFR
ErbB2
same
cell,
revealing
distinct
phases
each
RTK.
The
specificity
modularity
open
door
robust
biosensors
multiple
may
engineering
synthetic
receptors
response
programs.
npj Systems Biology and Applications,
Год журнала:
2024,
Номер
10(1)
Опубликована: Июнь 4, 2024
Abstract
Understanding
the
dynamics
of
intracellular
signaling
pathways,
such
as
ERK1/2
(ERK)
and
Akt1/2
(Akt),
in
context
cell
fate
decisions
is
important
for
advancing
our
knowledge
cellular
processes
diseases,
particularly
cancer.
While
previous
studies
have
established
associations
between
ERK
Akt
activities
proliferative
fate,
heterogeneity
single-cell
responses
adds
complexity
to
this
understanding.
This
study
employed
a
data-driven
approach
address
challenge,
developing
machine
learning
models
trained
on
dataset
growth
factor-induced
activity
time
courses
single
cells,
predict
division
events.
The
most
predictive
were
developed
by
applying
discrete
wavelet
transforms
(DWTs)
extract
low-frequency
features
from
courses,
followed
using
Ensemble
Integration,
data
integration
modeling
framework.
results
demonstrated
that
these
effectively
predicted
events
MCF10A
cells
(F-measure=0.524,
AUC=0.726).
found
be
more
than
Akt,
but
combination
both
measurements
further
enhanced
performance.
model`s
performance
also
generalized
predicting
RPE
indicating
potential
applicability
methodology
across
different
biological
contexts.
Interpretation
suggested
throughout
cycle,
rather
immediately
after
factor
stimulation,
associated
with
likelihood
division.
Overall,
work
contributes
insights
into
power
intra-cellular
decisions,
highlights
approaches
unraveling
complex
behaviors.