ABSTRACT
Sex
determination
and
differentiation
are
fundamental
processes
that
not
only
essential
for
fertility
but
also
influence
the
development
of
many
other
organs,
hence,
important
species
diversity
survival.
In
mammals,
sex
is
determined
by
inheritance
an
X
or
a
Y
chromosome
from
father.
The
harbours
testis-determining
gene
SRY,
it
has
long
been
thought
its
absence
sufficient
ovarian
development.
Consequently,
pathway
treated
as
default
pathway,
in
sense
ovaries
do
have
need
female-determining
factor.
Recently,
factor
identified
mouse
master
regulator
Interestingly,
this
scenario
was
predicted
early
1983.
Review,
we
discuss
model
1983,
how
mechanisms
genes
currently
known
to
be
mammals
changed
supported
model,
finally,
reflect
on
what
these
findings
might
mean
vertebrates.
Accurate
specification
of
female
and
male
germ
cells
during
embryonic
development
is
critical
for
sexual
reproduction.
Primordial
(PGCs)
are
the
bipotential
precursors
mature
gametes
that
commit
to
an
oogenic
or
spermatogenic
fate
in
response
sex-determining
cues
from
fetal
gonad.
The
processes
required
PGCs
integrate
respond
signals
somatic
environment
gonads
not
understood.
In
this
study,
we
developed
first
single-nucleus
multiomics
map
chromatin
accessibility
gene
expression
murine
PGC
both
XX
XY
embryos.
Profiling
cell-type
specific
transcriptomes
regions
open
same
cell
captured
molecular
signatures
networks
underlying
sex
determination.
Joint
RNA
ATAC
data
single
resolved
previously
unreported
subpopulations
cataloged
a
multimodal
reference
atlas
differentiating
clusters.
We
discovered
regulatory
element
precedes
development,
suggesting
changes
may
prime
lineage
commitment
prior
differentiation.
Similarly,
found
dimorphism
increased
temporally
PGCs.
Combining
sequencing
data,
computationally
mapped
cohort
transcription
factors
regulate
sexually
dimorphic
genes
For
example,
enriched
factors,
TFAP2c,
TCFL5,
GATA2,
MGA,
NR6A1,
TBX4,
ZFX.
Sex-specific
enrichment
forkhead-box
POU6
families
was
also
observed
Finally,
determined
temporal
patterns
WNT,
BMP,
RA
signaling
determination,
our
discovery
analyses
identified
potentially
new
communication
pathways
between
supporting
Our
results
illustrate
diversity
involved
programming
towards
sex-specific
fate.
Nucleic Acids Research,
Год журнала:
2025,
Номер
53(3)
Опубликована: Янв. 24, 2025
The
ovarian
reserve
defines
female
reproductive
lifespan,
which
in
humans
spans
decades
due
to
the
maintenance
of
meiotic
arrest
non-growing
oocytes
(NGOs)
residing
primordial
follicles.
Unknown
is
how
chromatin
state
NGOs
established
enable
long-term
reserve.
Here,
we
show
that
a
remodeler,
CHD4,
member
Nucleosome
Remodeling
and
Deacetylase
(NuRD)
complex,
establishes
states
required
for
formation
Conditional
loss
CHD4
perinatal
mouse
results
acute
death
depletion
closed
at
regulatory
elements
pro-apoptotic
genes
prevent
cell
specific
prophase
I
facilitate
transition
from
meiotically-arrested
NGOs.
In
male
germ
cells,
genes,
allowing
survival.
These
demonstrate
role
defining
ensures
survival,
thereby
enabling
both
cells.
Advanced Science,
Год журнала:
2025,
Номер
unknown
Опубликована: Фев. 25, 2025
Klinefelter
syndrome
(KS),
characterized
by
the
presence
of
at
least
one
extra
X-chromosome,
is
a
common
cause
male
infertility.
However,
mechanism
underlying
failure
germline
specification
not
well
studied.
Intriguingly,
differentiation
efficiency
female
human
pluripotent
stem
cells
(hPSCs)
often
lower
than
that
male.
This
study
investigates
how
X-linked
gene
dosage
affects
primordial
germ
cell-like
(hPGCLCs)
in
both
healthy
and
diseased
conditions.
work
reveals
genes
play
multifaceted
role
against
fate
competency
to
hPGCLCs,
with
escape
IGSF1
CHRDL1
inhibiting
TGF-beta/Activin
A
BMP
pathways,
respectively.
Notably,
this
identifies
previously
unrecognized
SOX2,
upregulated
USP9X,
elucidating
species-specific
function
mammalian
germline.
The
USP9X-SOX2
regulatory
axis
profoundly
influenced
cellular
metabolism,
mitochondrial
morphology,
progenitor
competence
hPGCLCs
specification.
Furthermore,
inability
downregulate
SOX2
upregulate
SOX17
response
signaling
impedes
downstream
activation
due
motif
binding
competition.
These
findings
shed
novel
insights
into
divergent
roles
versus
mammals,
effects.
results
offer
potential
applications
for
improving
induction
facilitating
disease
mechanistic
studies.
ABSTRACT
Sex
determination
and
differentiation
are
fundamental
processes
that
not
only
essential
for
fertility
but
also
influence
the
development
of
many
other
organs,
hence,
important
species
diversity
survival.
In
mammals,
sex
is
determined
by
inheritance
an
X
or
a
Y
chromosome
from
father.
The
harbours
testis-determining
gene
SRY,
it
has
long
been
thought
its
absence
sufficient
ovarian
development.
Consequently,
pathway
treated
as
default
pathway,
in
sense
ovaries
do
have
need
female-determining
factor.
Recently,
factor
identified
mouse
master
regulator
Interestingly,
this
scenario
was
predicted
early
1983.
Review,
we
discuss
model
1983,
how
mechanisms
genes
currently
known
to
be
mammals
changed
supported
model,
finally,
reflect
on
what
these
findings
might
mean
vertebrates.
