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Complex Cooperative Functions of Heparan Sulfate Proteoglycans Shape Nervous System Development in Caenorhabditis elegans.
[kallmann syndrome]
The
development
of
the
nervous
system
is
a
complex
process
requiring
the
integration
of
numerous
molecular
cues
to
form
functional
circuits
.
Many
cues
are
regulated
by
heparan
sulfates
,
a
class
of
linear
glycosaminoglycan
polysaccharides
.
These
sugars
contain
distinct
modification
patterns
that
regulate
protein-protein
interactions
.
Misexpressing
the
homolog
of
KAL-
1
/
anosmin-
1
,
a
neural
cell
adhesion
molecule
mutant
in
Kallmann
syndrome
,
in
Caenorhabditis
elegans
causes
a
highly
penetrant
,
heparan
sulfate-dependent
axonal
branching
phenotype
in
AIY
interneurons
.
In
an
extended
forward
genetic
screen
for
modifiers
of
this
phenotype
,
we
identified
alleles
in
new
as
well
as
previously
identified
genes
involved
in
HS
biosynthesis
and
modification
,
namely
the
xylosyltransferase
sqv-
6
,
the
HS
-
6
-
O-
sulfotransferase
hst-
6
,
and
the
HS
-
3
-
O-
sulfotransferase
hst-
3
.
2
.
Cell-
specific
rescue
experiments
showed
that
different
HS
biosynthetic
and
modification
enzymes
can
be
provided
cell-nonautonomously
by
different
tissues
to
allow
kal-
1
-
dependent
branching
of
AIY
.
In
addition
,
we
show
that
heparan
sulfate
proteoglycan
core
proteins
that
carry
the
heparan
sulfate
chains
act
genetically
in
a
highly
redundant
fashion
to
mediate
kal-
1
-
dependent
branching
in
AIY
neurons
.
Specifically
,
lon-
2
/
glypican
and
unc-
52
/
perlecan
act
in
parallel
genetic
pathways
and
display
synergistic
interactions
with
sdn-
1
/
syndecan
to
mediate
kal-
1
function
.
Because
all
of
these
heparan
sulfate
core
proteins
have
been
shown
to
act
in
different
tissues
,
these
studies
indicate
that
KAL-
1
/
anosmin-
1
requires
heparan
sulfate
with
distinct
modification
patterns
of
different
cellular
origin
for
function
.
Our
results
support
a
model
in
which
a
three
-dimensional
scaffold
of
heparan
sulfate
mediates
KAL-
1
/
anosmin-
1
and
intercellular
communication
through
complex
and
cooperative
interactions
.
In
addition
,
the
genes
we
have
identified
could
contribute
to
the
etiology
of
Kallmann
syndrome
in
humans
.
Diseases
Validation
Diseases presenting
"highly penetrant"
symptom
22q11.2 deletion syndrome
kallmann syndrome
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