Oxford University Press eBooks,
Год журнала:
2024,
Номер
unknown, С. 1216 - 1218
Опубликована: Май 1, 2024
Abstract
Attention-deficit/hyperactivity
disorder
(ADHD)
is
a
common
comorbidity
in
patients
with
epilepsy.
A
polygenic
predisposition
likely
interacts
environmental
factors
to
determine
the
ultimate
likelihood
and
severity
of
comorbid
attention
deficits.
Epilepsy
syndromes
such
as
Dravet
syndrome,
juvenile
myoclonic
epilepsy,
childhood
absence
fragile
X
syndrome
all
have
high
prevalence
ADHD.
Many
these
epilepsy
are
associated
monogenic
mutations
that
been
implicated
inhibitory
neurotransmission
(Scn1a,
GABRA1,
Cacna1a,
SNAP25,
FMR1,
respectively).
Monogenic
rodent
models
carrying
genetic
recapitulated
varying
degrees
hyperactivity,
Specifically
testing
various
aspects
rodents
has
performed
validated
procedures
Attention
Set-Shifting
task
(ASST)
or
5-Choice
Serial
Reaction
Time
(5-CSRTT).
Recent
studies
found
cell-type-specific
dysfunction
subsets
neurons,
most
prominently
parvalbumin-expressing
neurons.
This
underlying
leads
symptomatic
expression
both
seizures
Both
can
be
treated
independently
antiseizure
drugs
stimulant
therapy,
respectively.
However,
there
remain
no
specific
therapies
for
epileptogenic
insult.
Further
should
aim
combine
pathophysiological
insight
gained
from
targeted
on
genetic,
molecular,
cellular,
and/or
network
levels.
These
then
screened
mutant
using
ASST
5-CSRTT
identify
greatest
chance
improving
quality
life
Protein-coding
differences
between
species
often
fail
to
explain
phenotypic
diversity,
suggesting
the
involvement
of
genomic
elements
that
regulate
gene
expression
such
as
enhancers.
Identifying
associations
enhancers
and
phenotypes
is
challenging
because
enhancer
activity
can
be
tissue-dependent
functionally
conserved
despite
low
sequence
conservation.
We
developed
Tissue-Aware
Conservation
Inference
Toolkit
(TACIT)
associate
candidate
with
species'
using
predictions
from
machine
learning
models
trained
on
specific
tissues.
Applying
TACIT
motor
cortex
parvalbumin-positive
interneuron
neurological
revealed
dozens
enhancer-phenotype
associations,
including
brain
size-associated
interact
genes
implicated
in
microcephaly
or
macrocephaly.
provides
a
foundation
for
identifying
associated
evolution
any
convergently
evolved
phenotype
large
group
aligned
genomes.
Cell stem cell,
Год журнала:
2023,
Номер
30(10), С. 1331 - 1350.e11
Опубликована: Окт. 1, 2023
Mesial
temporal
lobe
epilepsy
(MTLE)
is
the
most
common
focal
epilepsy.
One-third
of
patients
have
drug-refractory
seizures
and
are
left
with
suboptimal
therapeutic
options
such
as
brain
tissue-destructive
surgery.
Here,
we
report
development
characterization
a
cell
therapy
alternative
for
drug-resistant
MTLE,
which
derived
from
human
embryonic
stem
line
comprises
cryopreserved,
post-mitotic,
medial
ganglionic
eminence
(MGE)
pallial-type
GABAergic
interneurons.
Single-dose
intrahippocampal
delivery
interneurons
in
mouse
model
chronic
MTLE
resulted
consistent
mesiotemporal
seizure
suppression,
animals
becoming
seizure-free
surviving
longer.
The
grafted
dispersed
locally,
functionally
integrated,
persisted
long
term,
significantly
reduced
dentate
granule
dispersion,
pathological
hallmark
MTLE.
These
disease-modifying
effects
were
dose-dependent,
broad
range.
No
adverse
observed.
findings
support
an
ongoing
phase
1/2
clinical
trial
(NCT05135091)
Deciphering
how
the
human
striatum
develops
is
necessary
for
understanding
diseases
that
affect
this
region.
To
decode
transcriptional
modules
regulate
structure
during
development,
we
compiled
a
catalog
of
1116
long
intergenic
noncoding
RNAs
(lincRNAs)
identified
de
novo
and
then
profiled
96,789
single
cells
from
early
fetal
striatum.
We
found
D1
D2
medium
spiny
neurons
(D1-
D2-MSNs)
arise
common
progenitor
lineage
commitment
established
postmitotic
transition,
across
pre-MSN
phase
exhibits
continuous
spectrum
fate
determinants.
uncovered
cell
type-specific
gene
regulatory
networks
validated
through
in
silico
perturbation.
Finally,
human-specific
lincRNAs
contribute
to
phylogenetic
divergence
humans.
This
work
delineates
cellular
hierarchies
governing
MSN
commitment.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Фев. 1, 2024
Mutations
in
aristaless-related
homeobox
(
ARX
)
are
associated
with
neurodevelopmental
disorders
including
developmental
epilepsies,
intellectual
disabilities,
and
autism
spectrum
disorders,
or
without
brain
malformations.
Aspects
of
these
have
been
linked
to
abnormal
cortical
interneuron
(cIN)
development
function.
To
further
understand
ARX's
role
cIN
development,
multiple
Arx
mutant
mouse
lines
were
interrogated.
We
found
that
is
critical
for
controlling
numbers
distribution,
especially,
the
developing
marginal
zone
(MZ).
Single
cell
transcriptomics
ChIP-seq,
combined
functional
studies,
revealed
directly
indirectly
regulates
genes
involved
proliferation
cycle
(e.g.,
Bub3
,
Cspr3
),
fate
specification
Nkx2.1
Maf
Mef2c
migration
Lmo1
Cxcr4
Nrg1
ErbB4
).
Our
data
suggest
MZ
stream
defects
primarily
result
from
disordered
cell-cell
communication.
Together
our
findings
provide
new
insights
into
mechanisms
underlying
how
they
disrupted
several
disorders.
Nucleic Acids Research,
Год журнала:
2021,
Номер
49(13), С. 7437 - 7456
Опубликована: Июнь 22, 2021
Abstract
Despite
its
prominence,
the
mechanisms
through
which
tumor
suppressor
p53
regulates
most
genes
remain
unclear.
Recently,
regulatory
factor
X
7
(RFX7)
emerged
as
a
of
lymphoid
neoplasms,
but
regulation
and
target
mediating
suppression
unknown.
Here,
we
identify
novel
p53-RFX7
signaling
axis.
Integrative
analysis
RFX7
DNA
binding
landscape
RFX7-regulated
transcriptome
in
three
distinct
cell
systems
reveals
that
directly
controls
multiple
established
suppressors,
including
PDCD4,
PIK3IP1,
MXD4,
PNRC1,
across
types
is
missing
link
for
their
activation
response
to
stress.
gene
expression
correlates
with
differentiation
better
prognosis
numerous
cancer
types.
Interestingly,
find
sensitizes
cells
Doxorubicin
by
promoting
apoptosis.
Together,
our
work
establishes
RFX7’s
role
ubiquitous
regulator
growth
fate
determination
key
node
transcriptional
program.
Oxford University Press eBooks,
Год журнала:
2024,
Номер
unknown, С. 1016 - 1024
Опубликована: Май 1, 2024
Abstract
GABAergic
interneurons
(INs)
constitute
20%–30%
of
the
pallial
(neocortical
and
hippocampal)
neurons.
They
are
main
source
cortical
hippocampal
synaptic
inhibitory
signals.
Distinct
IN
subtypes
inhibit
different
cellular
subcellular
components
circuits.
INs
generated
from
subdomains
embryonic
basal
ganglia
(ganglionic
eminences,
GEs).
Transcription
factors
(TFs)
through
regulatory
elements
(REs)
that
they
bind
integral
in
programming
gene
expression
a
temporally
spatially
diverse
manner.
This
then
programs
cell
fate-commitment,
differentiation,
migration,
maturation
to
generate
subtypes.
Of
note,
prevailing
molecular
genetic
knowledge
about
development
has
been
established
by
decades
studies
rodent
is
hypothesized
reflect
many
processes
common
mammals.
Research
on
human
primate
brain
will
test
this
hypothesis
also
offers
opportunity
identify
species-specific
variations.
In
chapter,
we
focus
discoveries
derived
mouse
research.
chapter
reviews
histology
GEs,
fate-mapping
tools,
TFs
control
regional
patterning
regulate
maturation,
REs
involved
development.
Frontiers in Genetics,
Год журнала:
2025,
Номер
16
Опубликована: Апрель 9, 2025
Introduction:
Transcriptional
regulation
is
an
important
process
wherein
non-protein
coding
enhancer
sequences
play
a
key
role
in
determining
cell
type
identity
and
phenotypic
diversity.
In
neural
tissue,
these
gene
regulatory
processes
are
crucial
for
coordinating
plethora
of
interconnected
regionally
specialized
types,
ensuring
their
synchronized
activity
generating
behavior.
Recognizing
the
intricate
interplay
brain
imperative,
as
mounting
evidence
links
neurodevelopment
neurological
disorders
to
non-coding
genome
regions.
While
genome-wide
association
studies
swiftly
identifying
human
disease-associated
loci,
decoding
mechanisms
challenging
due
causal
variant
ambiguity
specific
tissue
impacts.
Methods:
Massively
parallel
reporter
assays
(MPRAs)
widely
used
culture
study
regions,
linking
sequence
differences
tissue-specific
function.
However,
widespread
use
animals
encounters
significant
challenges,
including
insufficient
viral
library
delivery
quantification,
irregular
transduction
rates,
injection
site
inflammation
disrupting
expression.
Here,
we
introduce
systemic
MPRA
(sysMPRA)
address
challenges
through
intravenous
AAV
delivery.
Results:
We
demonstrate
successful
into
diverse
mouse
tissues,
efficiently
specificity
candidate
enhancers
aligning
well
with
predictions
from
machine
learning
models.
highlight
that
sysMPRA
effectively
uncovers
effects
stemming
disruption
MEF2C
transcription
factor
binding
sites,
single-nucleotide
polymorphisms,
consequences
genetic
variations
associated
late-onset
Alzheimer's
disease.
Conclusion:
SysMPRA
effective
delivering
method
simultaneously
determines
transcriptional
functions
hundreds
vivo
across
multiple
tissues.
