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GnRH neuronal migration and olfactory bulb neurite outgrowth are dependent on FGF receptor 1 signaling, specifically via the PI3K p110α isoform in chick embryo.
[kallmann syndrome]
Fibroblast
growth
factor
(
FGF
)
signaling
is
essential
for
both
olfactory
bulb
(
OB
)
morphogenesis
and
the
specification
,
migration
,
and
maturation
of
the
GnRH-secreting
neurons
.
Disruption
of
FGF
signaling
contributes
to
Kallmann
syndrome
characterized
by
both
anosmia
and
sexual
immaturity
.
However
,
several
unanswered
questions
remain
as
to
which
specific
FGF
receptor
(
FGFR
)
-
1
signaling
pathways
are
necessary
for
OB
and
GnRH
neuronal
development
.
Here
,
using
pharmacological
phosphatidylinositol
3
-
kinase
(
PI
3
K
)
isoform-
specific
inhibitors
,
we
demonstrate
a
central
role
for
the
PI
3
K
p
110
α
isoform
as
a
downstream
effector
of
FGFR
1
signaling
for
both
GnRH
neuronal
migration
and
OB
development
.
We
show
that
signaling
via
the
PI
3
K
p
110
α
isoform
is
required
for
GnRH
neuronal
migration
in
explant
cultures
of
embryonic
day
(
E
)
4
chick
olfactory
placodes
.
We
also
show
that
in
ovo
administration
of
LY
294002
,
a
global
PI
3
K
inhibitor
as
well
as
an
inhibitor
to
the
PI
3
K
p
110
α
isoform
into
the
olfactory
placode
of
E
3
chick
embryo
impairs
GnRH
neuronal
migration
toward
the
forebrain
.
In
contrast
,
in
ovo
PI
3
K
inhibitor
treatment
produced
no
obvious
defects
on
primary
olfactory
sensory
neuron
axonal
targeting
and
bundle
formation
.
We
also
demonstrate
that
anosmin-
1
and
FGF
2
induced
neuronal
migration
of
immortalized
human
embryonic
GnRH
neuroblast
cells
(
FNC-B
4
-
hTERT
)
is
mediated
by
modulating
FGFR
1
signaling
via
the
PI
3
K
p
110
α
isoform
,
specifically
through
phosphorylation
of
the
PI
3
K
downstream
effectors
,
Akt
and
glycogen
synthase
kinase-
3
β
.
Finally
,
we
show
that
neurite
outgrowth
and
elongation
of
OB
neurons
in
E
10
chick
OB
explants
are
also
dependent
on
the
PI
3
K
p
110
α
isoform
downstream
of
FGFR
1
.
This
study
provides
mechanistic
insight
into
the
etiology
of
Kallmann
syndrome
.
Diseases
Validation
Diseases presenting
"neuronal development"
symptom
kallmann syndrome
monosomy 21
zellweger syndrome
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