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Profiling, Bioinformatic, and Functional Data on the Developing Olfactory/GnRH System Reveal Cellular and Molecular Pathways Essential for This Process and Potentially Relevant for the Kallmann Syndrome.
[kallmann syndrome]
During
embryonic
development
,
immature
neurons
in
the
olfactory
epithelium
(
OE
)
extend
axons
through
the
nasal
mesenchyme
,
to
contact
projection
neurons
in
the
olfactory
bulb
.
Axon
navigation
is
accompanied
by
migration
of
the
GnRH
+
neurons
,
which
enter
the
anterior
forebrain
and
home
in
the
septo-
hypothalamic
area
.
This
process
can
be
interrupted
at
various
points
and
lead
to
the
onset
of
the
Kallmann
syndrome
(
KS
)
,
a
disorder
characterized
by
anosmia
and
central
hypogonadotropic
hypogonadism
.
Several
genes
has
been
identified
in
human
and
mice
that
cause
KS
or
a
KS
-like
phenotype
.
In
mice
a
set
of
transcription
factors
appears
to
be
required
for
olfactory
connectivity
and
GnRH
neuron
migration
;
thus
we
explored
the
transcriptional
network
underlying
this
developmental
process
by
profiling
the
OE
and
the
adjacent
mesenchyme
at
three
embryonic
ages
.
We
also
profiled
the
OE
from
embryos
null
for
Dlx
5
,
a
homeogene
that
causes
a
KS
-like
phenotype
when
deleted
.
We
identified
20
interesting
genes
belonging
to
the
following
categories
:
(
1
)
transmembrane
adhesion
/
receptor
,
(
2
)
axon-glia
interaction
,
(
3
)
scaffold
/
adapter
for
signaling
,
(
4
)
synaptic
proteins
.
We
tested
some
of
them
in
zebrafish
embryos
:
the
depletion
of
five
(
of
six
)
Dlx
5
targets
affected
axonal
extension
and
targeting
,
while
three
(
of
three
)
affected
GnRH
neuron
position
and
neurite
organization
.
Thus
,
we
confirmed
the
importance
of
cell-cell
and
cell-matrix
interactions
and
identified
new
molecules
needed
for
olfactory
connection
and
GnRH
neuron
migration
.
Using
available
and
newly
generated
data
,
we
predicted
/
prioritized
putative
KS
-disease
genes
,
by
building
conserved
co
-expression
networks
with
all
known
disease
genes
in
human
and
mouse
.
The
results
show
the
overall
validity
of
approaches
based
on
high
-throughput
data
and
predictive
bioinformatics
to
identify
genes
potentially
relevant
for
the
molecular
pathogenesis
of
KS
.
A
number
of
candidate
will
be
discussed
,
that
should
be
tested
in
future
mutation
screens
.
Diseases
Validation
Diseases presenting
"predictive bioinformatics to identify genes potentially relevant for the molecular pathogenesis of ks"
symptom
kallmann syndrome
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