bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Июнь 29, 2024
ABSTRACT
The
inactivation
of
Rbm24,
an
RNA-binding
protein,
results
in
the
degeneration
cochlear
outer
hair
cells
(OHCs)
during
postnatal
period.
However,
specific
molecular
mechanisms
underlying
this
OHC
death
remain
elusive.
To
address
this,
we
conducted
a
comprehensive
analysis
comparing
gene
profiles
wild-type
OHCs
to
those
lacking
Rbm24
(
-/-
)
at
day
7
(P7).
Our
revealed
that
overall
differentiation
program
is
delayed
absence
Rbm24.
Furthermore,
expression
Insm1,
crucial
factor
for
development
normally
switched
off
by
P2,
remains
prolonged
OHCs.
Interestingly,
when
Insm1
overexpressed,
it
also
leads
death.
Significantly,
much
less
severe
both
and
are
simultaneously
inactivated.
These
findings
shed
light
on
important
role
repressing
its
impact
survival.
study
provides
valuable
insights
into
complex
genetic
signaling
pathways
involved
development.
Annual Review of Neuroscience,
Год журнала:
2024,
Номер
47(1), С. 1 - 20
Опубликована: Фев. 16, 2024
Auditory
processing
in
mammals
begins
the
peripheral
inner
ear
and
extends
to
auditory
cortex.
Sound
is
transduced
from
mechanical
stimuli
into
electrochemical
signals
of
hair
cells,
which
relay
information
via
primary
neurons
cochlear
nuclei.
Information
subsequently
processed
superior
olivary
complex,
lateral
lemniscus,
inferior
colliculus
projects
cortex
medial
geniculate
body
thalamus.
Recent
advances
have
provided
valuable
insights
development
functioning
structures,
complementing
our
understanding
physiological
mechanisms
underlying
processing.
This
comprehensive
review
explores
genetic
required
for
system
cochlea
We
highlight
transcription
factors
other
genes
with
key
recurring
interacting
roles
guiding
organization.
Understanding
these
gene
regulatory
networks
holds
promise
developing
novel
therapeutic
strategies
hearing
disorders,
benefiting
millions
globally.
Cochlear
inner
hair
cells
(IHCs)
and
outer
(OHCs)
require
different
transcription
factors
for
their
cell
fate
stabilization
survival,
suggesting
separate
mechanisms
are
involved.
Here,
we
found
that
the
factor
Casz1
was
crucial
early
IHC
consolidation
OHC
survival
during
mouse
development.
Loss
of
resulted
in
transdifferentiation
IHCs
into
OHCs,
without
affecting
production.
However,
long-term
compromised
mutant
mice.
In
addition,
Gata3
down-regulated
-deleted
overexpressing
partially
rescued
properties,
numbers,
hearing
Thus,
plays
critical
roles
could
potentially
provide
a
lead
therapies
aimed
at
regenerating
both
OHCs.
Frontiers in Cell and Developmental Biology,
Год журнала:
2024,
Номер
12
Опубликована: Март 18, 2024
In
electroreceptive
jawed
vertebrates,
embryonic
lateral
line
placodes
give
rise
to
electrosensory
ampullary
organs
as
well
mechanosensory
neuromasts.
Previous
reports
of
shared
gene
expression
suggest
that
conserved
mechanisms
underlie
electroreceptor
and
hair
cell
development
electroreceptors
evolved
a
transcriptionally
related
“sister
type”
cells.
We
previously
identified
only
one
transcription
factor
gene,
Neurod4
,
organ-restricted
in
the
developing
system
chondrostean
ray-finned
fish,
Mississippi
paddlefish
(
Polyodon
spathula
).
The
other
16
genes
we
validated
were
expressed
both
Here,
used
our
published
organ-enriched
gene-set
(arising
from
differential
bulk
RNA-seq
late-larval
paddlefish),
together
with
candidate
approach,
identify
25
more
experimentally
tractable
chondrostean,
sterlet
Acipenser
ruthenus
small
sturgeon),
and/or
paddlefish.
Thirteen
are
neuromasts,
consistent
conservation
molecular
mechanisms.
Seven
electrosensory-restricted
on
head
Irx5
Irx3
Insm1
Sp5
Satb2
Mafa
Rorc
),
five
first-reported
mechanosensory-restricted
Foxg1
Sox8
Isl1
Hmx2
Rorb
However,
reported,
is
neuromasts
catshark
Scyliorhinus
canicula
suggesting
existence
lineage-specific
differences
between
cartilaginous
fishes.
Overall,
results
support
hypothesis
develop
via
largely
transcriptional
mechanisms,
multiple
factors
potentially
involved
formation
versus
organs.
Cochlear
inner
hair
cells
(IHCs)
are
primary
sound
receptors,
and
therefore
a
target
for
developing
treatments
hearing
impairment.
IHC
regeneration
in
vivo
has
been
widely
attempted,
although
not
yet
the
IHC-damaged
cochlea.
Moreover,
extent
to
which
new
IHCs
resemble
wild-type
remains
unclear,
as
is
ability
of
improve
hearing.
Here,
we
have
developed
an
mouse
model
wherein
were
pre-damaged
nonsensory
supporting
transformed
into
by
ectopically
expressing
Atoh1
transiently
Tbx2
permanently.
Notably,
expressed
functional
marker
vGlut3
presented
similar
transcriptomic
electrophysiological
properties
IHCs.
Furthermore,
formation
efficiency
maturity
higher
than
those
previously
reported,
marked
improvement
was
achieved,
at
least
partly
due
defective
mechanoelectrical
transduction
(MET)
Thus,
successfully
regenerated
resembling
many
respects
damaged
Our
findings
suggest
that
MET
critical
barrier
prevents
restoration
capacity
should
thus
facilitate
future
studies.
Journal of Neuroscience,
Год журнала:
2024,
Номер
44(23), С. e1751232024 - e1751232024
Опубликована: Апрель 30, 2024
The
mouse
auditory
organ
cochlea
contains
two
types
of
sound
receptors:
inner
hair
cells
(IHCs)
and
outer
(OHCs).
Tbx2
is
expressed
in
IHCs
but
repressed
OHCs,
neonatal
OHCs
that
misexpress
transdifferentiate
into
IHC-like
cells.
However,
the
extent
this
switch
from
to
underlying
molecular
mechanism
remain
poorly
understood.
Furthermore,
whether
can
transform
fully
mature
adult
unknown.
Here,
our
single-cell
transcriptomic
analysis
revealed
misexpressing
Tbx2,
85.6%
IHC
genes,
including
Slc17a8
,
are
upregulated,
only
38.6%
OHC
Ikzf2
Slc26a5
downregulated.
This
suggests
cannot
reprogram
IHCs.
Moreover,
also
failed
completely
cochlear
progenitors
Lastly,
restoring
expression
alleviated
abnormalities
detected
Tbx2+
which
supports
notion
repression
by
contributes
transdifferentiation
Our
study
evaluates
effects
ectopic
on
lineage
development
at
distinct
stages
either
male
or
female
mice
provides
insights
how
disrupts
gene
profile
OHCs.
research
lays
groundwork
for
future
studies
regeneration.
Advanced Science,
Год журнала:
2024,
Номер
unknown
Опубликована: Июль 11, 2024
Cochlear
hair
cells
are
the
sensory
responsible
for
transduction
of
acoustic
signals.
In
mammals,
damaged
do
not
regenerate,
resulting
in
permanent
hearing
loss.
Reprogramming
surrounding
supporting
to
functional
represent
a
novel
strategy
restoration.
However,
cellular
processes
governing
efficient
and
cell
reprogramming
completely
understood.
Employing
mouse
cochlear
organoid
system,
detailed
metabolomic
characterizations
expanding
differentiating
organoids
performed.
It
is
found
that
differentiation
associated
with
increased
mitochondrial
electron
transport
chain
(ETC)
activity
reactive
oxidative
species
generation.
Transcriptome
metabolome
analyses
indicate
reduced
expression
oxidoreductases
tricyclic
acid
(TCA)
cycle
metabolites.
The
metabolic
decoupling
between
ETC
TCA
limits
availability
key
cofactors,
α-ketoglutarate
(α-KG)
nicotinamide
adenine
dinucleotide
(NAD
Hearing Research,
Год журнала:
2024,
Номер
448, С. 109035 - 109035
Опубликована: Май 19, 2024
The
sensory
epithelia
of
the
auditory
and
vestibular
systems
vertebrates
have
shared
developmental
evolutionary
histories.
However,
while
show
great
variation
across
vertebrates,
appear
seemingly
more
conserved.
An
exploration
current
knowledge
comparative
biology
amniote
utricle,
a
epithelium
that
senses
linear
acceleration,
shows
interesting
instances
variability
between
birds
mammals.
distribution
hair
cell
types,
position
line
bundle
polarity
reversal
properties
supporting
cells
marked
differences,
likely
impacting
function
regeneration
potential.
The Journal of Comparative Neurology,
Год журнала:
2024,
Номер
532(12)
Опубликована: Дек. 1, 2024
A
gene
cadre
orchestrates
the
normal
development
of
sensory
and
non-sensory
cells
in
inner
ear,
segregating
cochlea
with
a
distinct
tonotopic
sound
frequency
map,
similar
brain
projection,
five
vestibular
end-organs.
However,
role
genes
driving
ear
is
largely
unknown.
Here,
we
show
double
deletion
Iroquois
homeobox
3
5
transcription
factors
(Irx3/5
DKO)
leads
to
fusion
saccule
cochlear
base.
The
overlying
otoconia
tectorial
membranes
are
absent
Irx3/5
DKO
primary
auditory
neurons
project
fibers
both
hair
cells.
central
neuronal
projections
from
apex-base
contour
not
fully
segregated
into
dorsal
ventral
innervation
nucleus,
obliterating
characteristic
map.
Additionally,
reveals
pronounced
cochlear-apex-vestibular
"vestibular-cochlear"
nerve
(VCN)
bilateral
connection
that
less
noticeable
wild-type
control
mice.
Moreover,
incomplete
segregation
apex
base
expands
connect
nuclei.
results
suggest
mammalian
derived
lagena
reminiscent
sarcopterygians.
Thus,
Irx3
potential
evolutionary
branch-point
necessary
for
balance-sound
segregation,
which
fused
saccule-cochlea
organization.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2023,
Номер
unknown
Опубликована: Сен. 17, 2023
Abstract
The
cochlea,
the
auditory
organ,
contains
two
types
of
sound
receptors:
inner
hair
cells
(IHCs)
and
outer
(OHCs).
Tbx2
is
expressed
in
IHCs
but
repressed
OHCs.
neonatal
OHCs
with
misexpression
transdifferentiate
into
IHC-like
cells.
However,
extent
switch
from
to
underlying
molecular
mechanism
remain
poorly
understood.
Furthermore,
it
unknown
whether
can
transform
fully
mature
adult
In
this
study,
we
employ
single-cell
transcriptomic
analysis,
revealing
that
85.6%
IHC
genes,
including
Slc17a8
,
are
upregulated,
whereas
only
38.6%
OHC
Ikzf2
Slc26a5
downregulated
misexpression.
Thus,
our
findings
suggest
cannot
reprogram
IHCs,
contrary
previous
assumptions.
Consistently,
also
fails
cochlear
progenitors
IHCs.
Finally,
restoration
alleviates
abnormalities
present
Tbx2+
OHCs,
supporting
notion
repression
by
contributes
transdifferentiation
Overall,
study
reevaluates
effects
ectopic
expression
on
lineage
development
at
different
stages
provides
insights
how
disrupts
gene
profiles
This
research
lays
groundwork
for
future
studies
regeneration.
Significance
Statement
Understanding
genetic
mechanisms
govern
determination
stability
(OHCs)
would
provide
valuable
regenerating
damaged
manuscript,
conduct
vivo
conditional
overexpression
sensory
progenitors,
respectively.
Our
challenge
assumptions
alone
partially
destabilize
fates
convert
Specifically,
demonstrate
due
one
key
pathways
disrupting
fate.