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First published online 13 February 2008
doi: 10.1242/dev.007401
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Department of Cell Biology and Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA.
* Author for correspondence (e-mail: flanagan{at}hms.harvard.edu)
Accepted 9 January 2008
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SUMMARY |
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SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
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, were modulated by
both contactin 4 and NgCAM. In the developing retinotectal system, APP,
contactin 4 and NgCAM are expressed in the retina and tectum in suitable
locations to interact. Functional assays revealed regulatory effects of both
APP and contactin 4 on NgCAM-dependent growth of cultured retinal axons,
demonstrating specific functional interactions among these proteins. These
studies identify novel binding and functional interactions among proteins of
the APP, contactin and L1CAM families, with general implications for
mechanisms of APP action in neural development and disease.
Key words: Amyloid precursor protein, Axon, Contactin, L1CAM, Retina
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INTRODUCTION |
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TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
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-secretases, is
the major component of the plaques. Mutations in APP have been linked to
familial Alzheimer's disease, and the most widely accepted models of disease
etiology propose that Aβ aggregates or oligomers trigger a cascade of
events causing damage to neuronal connections and cell death
(Selkoe, 1999
;
Hardy and Selkoe, 2002;
Tanzi and Bertram, 2005;
Catalano et al., 2006).
The functions of APP in normal physiology and development are not well
understood. APP-deficient mice are viable and fertile, but have some
abnormalities, including susceptibility to seizures
(Steinbach et al., 1998) and a
defect in corpus callosum formation
(Magara et al., 1999),
indicating roles in neural development and function. Triple knockout mice for
APP and its two homologs, APLP1 (amyloid precursor like protein 1) and APLP2,
exhibit a cortical defect reminiscent of human type 2 lissencephaly,
suggesting a role in neuronal migration, and die perinatally, although the
exact reasons for this remain mysterious
(Herms et al., 2004).
Since its initial identification, APP was thought likely to be a receptor,
based on its transmembrane structure (Kang
et al., 1987). By analogy to Notch
(Mumm and Kopan, 2000), an APP
signaling pathway has been proposed where -secretase cleavage yields
the C-terminal CTF fragment, then -cleavage liberates the APP
intracellular domain to participate in downstream pathways
(Chan and Jan, 1998). Some
evidence has accumulated to support this model of signaling
(Cao and Sudhof, 2001;
Kimberly et al., 2001;
Kinoshita et al., 2002),
although some aspects remain controversial
(Cao and Sudhof, 2004;
Hass and Yankner, 2005;
Hebert et al., 2006). Several
cytoplasmic binding partners for APP have been identified, delineating
potential downstream pathways (Kerr and
Small, 2005). However, the key signaling mechanisms remain
unclear, especially as it is not clear which, if any, of the identified
extracellular binding partners for APP might function as a physiological
ligand.
In addition to the potential receptor function of APP, its cleaved
ectodomain, APPs, may function as a ligand. Numerous studies have shown
that APPs can modulate cell behaviors including neurite outgrowth,
synaptogenesis, neurogenesis and cell survival and proliferation
(Mattson, 1997;
Turner et al., 2003;
Caille et al., 2004). Distinct
domains of APPs have been implicated in these actions, suggesting the
existence of more than one receptor. To date, however, no cell-surface
receptor capable of mediating APPs-induced signaling has been
identified.
More than a decade of work has led to the identification of a number of
extracellular partners that can interact with APP, directly or indirectly.
Binding has been reported for extracellular matrix components, including
heparan sulfate (Multhaup,
1994; Small et al.,
1994), collagen (Beher et al.,
1996) and fibulin 1 (Ohsawa et
al., 2001); zinc and copper ions
(Turner et al., 2003); and the
lipoprotein receptors, scavenger receptor A
(Santiago-Garcia et al., 2001)
and LRP (Kounnas et al.,
1995). More recently identified extracellular proteins that can
interact with APP include F-spondin (also known as spondin 1)
(Ho and Sudhof, 2004;
Hoe et al., 2005),
Drosophila FASII (Ashley et al.,
2005), BRI2 (ITM2B)
(Fotinopoulou et al., 2005;
Matsuda et al., 2005), APLP1,
APLP2 and APP itself (Soba et al.,
2005), Notch family members
(Fassa et al., 2005;
Fischer et al., 2005;
Oh et al., 2005;
Chen et al., 2006), LRRTM3
(Majercak et al., 2006) and
NgR (RTN4R) (Park et al.,
2006). Some of these proteins can influence candidate downstream
signaling pathways or APP processing. However, these interactions have
generally not yet been characterized thoroughly with regard to whether they
have affinity and specificity in the range of cognate receptor-ligand
interactions, involve direct interaction with APP, and whether they can affect
cell behavior. There is also generally little evidence regarding potential
roles for these interactions in vertebrate neural development.
Contactins, which are GPI-anchored, and L1CAM family proteins, which are
transmembrane proteins, are members of the IgCAM (immunoglobulin-related cell
adhesion molecule) superfamily. Contactins and L1CAMs can bind one another, as
well as partially overlapping sets of other cell-surface or
extracellular-matrix proteins
(Sonderegger, 1997). L1CAM and
its chicken homolog NgCAM have been widely studied for functions in axon
growth, guidance and fasciculation
(Hortsch, 1996;
Sonderegger, 1997;
Maness and Schachner, 2007),
as have contactins 1 and 2 (Falk et al.,
2002). Contactins 3 (PANG/BIG-1) and 4 (BIG-2) are less well
characterized, although both can promote neurite outgrowth
(Connelly et al., 1994;
Yoshihara et al., 1994;
Yoshihara et al., 1995). Like
APP, contactin 4 and L1CAM are implicated in neurological disorders. Contactin
4 gene disruption is proposed to cause 3p deletion syndrome, involving mental
retardation (Fernandez et al.,
2004; Dijkhuizen et al.,
2006). Mutations in L1CAM cause CRASH syndrome, which includes
mental retardation and corpus callosum hypoplasia
(Fransen et al., 1995).
Here, we took the approach of initially testing embryonic chick brain for
APP-binding sites, and found particularly prominent binding on retinal axons
growing into the optic tectum, a well-characterized model of axon development
(McLaughlin and O'Leary, 2005;
Flanagan, 2006). We next
identified extracellular binding partners and found APP to have a direct high
affinity interaction with contactins 3 and 4. APP also associates, directly or
indirectly, with tectal NgCAM. APP, contactins and NgCAM are all expressed in
the retinotectal system. In functional assays of cultured retinal ganglion
cells (RGCs), contactin 4 and APP modulated axon behavior specifically in the
context of NgCAM-dependent axon growth, demonstrating functional interactions
among these proteins. Our studies of binding, expression and functional
effects on cell behavior identify novel interactions of APP, with general
implications for development and disease.
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MATERIALS AND METHODS |
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SUMMARY
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MATERIALS AND METHODS
RESULTS
DISCUSSION
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contains amino acids 18-612 of APP695; human in
Fig. 4, mouse elsewhere.
AP-APLP1 encodes residues 34-567 of human APLP1 (NM_005166). N-terminal
alkaline phosphatase (AP) fusion constructs were in APtag4
(Flanagan et al., 2000).
APP-HA contains full-length human APP695, then an HA tag, in pcDNA3.1 Zeo+. A
start codon was placed upstream of APP amino acid 597 for CTFβ, and 613
for CTF.
NgCAM-Fc encodes residues 1-1134 from pSCT-NgCAM, kindly provided by P.
Sonderegger (Buchstaller et al.,
1996), in pSecTagIg. Fusions of all six human contactins were full
length up to the GPI anchor site, followed by Fc, in IgTag2Eco. Accession
numbers and predicted GPI sites are: contactin 1 (NM_001843, 993); 2
(NM_005076, 1012); 3 (NM_020872, 1002); 4 (NM_175607, 1000); 5 (NM_014361,
1072); 6 (NM_014461, 999). Deletion constructs encode the following regions in
pSecTagIg: c3Ig1-4 (20-404), c3Ig5-6 (405-597), c3FN (598-1005), c4Ig1-4
(19-404), c4Ig5-6 (405-595), c4FN (596-1000). Contactin 4-AP contains residues
1-1000, then C-terminal AP, in APtag2. Chick contactin 4-myc-His contains
residues 1-1005 in pcDNA3.1/myc-His.
Chick in situ probes in pBluescript II SK(-) contain ORF nucleotides: APP (AF289218), 471-1218; NgCAM (Z75013), 2827-3759; contactin 3 (NM_414433), 2465-3277; contactin 4 (XM_414435), 418-1212.
Immunolocalization, RNA and affinity probe in situs
AP fusion proteins were used as in situ probes as described
(Flanagan et al., 2000). In
situ hybridization used 10-µm sections of E11.5 chick with detection by
AP-coupled anti-digoxigenin (Roche) or, for fluorescent in situs,
peroxidase-conjugated anti-digoxigenin antibody (Roche) then Alexa Fluor 488
with tyramide amplification (Molecular Probes). Immunolocalization used rabbit
anti-GAP43 (Novus Biologicals), or goat anti-APP (44-63) (Calbiochem), then
fluorescent secondary antibodies (Molecular Probes).
AP and Fc fusion proteins
Fusion proteins were produced in transiently transfected 293T cells
(Flanagan et al., 2000). For
axon growth experiments, fusion proteins were produced in Opti-MEM plus ITS-A
(Invitrogen), then AP fusions were concentrated 10-fold using Amicon Centricon
(Millipore), or Fc fusions were purified with Protein A-Sepharose beads (4
Fast Flow, Amersham).
Protein purifications from brain
For purification of APP-binding proteins, tecta from E12.5 chick embryos
(approximately 100 for small-scale experiments, 1200 for large-scale) were
treated as follows, at room temperature unless indicated: Hank's buffered salt
solution (HBSS) wash; 0.2 mg/ml EZ-link NHS-LC-Biotin (Pierce) in HH (HBSS
with 20 mM HEPES, pH 7.0), 45 minutes; 50 mM Tris pH 7.5 in HH, 20 minutes;
HBAH (HBSS with 0.5 mg/ml BSA, 0.05% sodium azide and 20 mM HEPES, pH 7.0)
wash; AP fusion-containing conditioned media, at least 90 minutes; ice-cold
HBAH, six washes; ice-cold HBSS, six washes; 0.5 mg/ml DTSSP (Pierce) in HH,
45 minutes; 50 mM Tris pH 7.5 in HH, 20 minutes; Lysis buffer (0.5% sodium
deoxycholate, 0.5% Triton X-114 and 0.05% SDS in PBS) plus protease inhibitors
(5 mM EDTA plus cOmplete, Roche), 45 minutes, ice. Supernatant was cleared
100,000 g, 4°C, then incubated overnight at 4°C with
anti-AP (MIA1801, Seradyn) beads as described
(Flanagan et al., 2000). Beads
were washed with ice-cold Lysis buffer, then Wash buffer (0.1% Triton X-100 in
PBS), eluted with 100 mM glycine, 150 mM NaCl, pH 3.0, then buffered with 100
mM Tris pH 8.0. For SDS-PAGE, proteins were precipitated with 10% TCA. For 2D
gels, sample was boiled 15 minutes in 100 mM DTT, then incubated with 9.25
mg/ml iodoacetamide, 15 minutes, before TCA precipitation.
For purification of tectal surface proteins, 800 E12.5 chick tecta were incubated in HBSS (one wash); 1 mg/ml Sulfo-NHS-SS-Biotin (Pierce) in HH, 1 hour; 50 mM Tris pH 7.5 in HH, 20 minutes; then HBSS (several washes). Tectal lysis and clearing were as above, followed by overnight incubation at 4°C with NeutrAvidin beads (Pierce). Beads were washed with the following buffers: Lysis, Wash, High salt wash (1 M NaCl, 20 mM HEPES pH 7.0 and 0.1% Triton X-100), then Wash. The biotinylation reagent was cleaved in 100 mM DTT (65°C, 40 minutes), then protein was TCA precipitated.
The ZOOM IPGRunner system (Invitrogen) was used for 2D gels, using pH 3-10
strips and 4-20% Tris-glycine gels. Sample buffer was from the 2D Insoluble
Protein Sample Prep Kit (Pierce) with carrier ampholytes (Invitrogen), 20 mM
DTT and 0.02 mg/ml bromophenol blue. Silver staining was as described
(Shevchenko et al., 1996). For
western blots, biotin was detected with horseradish peroxidase-conjugated
NeutrAvidin (Pierce).
Antibodies to test candidate tectal proteins were anti-PSA-NCAM (Amersham),
anti-chick NCAM-1 (Amersham), anti-tenascin (Chemicon), anti-neogenin (R&D
systems), anti-contactin 1 (BD Biosciences) and three chick NgCAM antibodies:
mouse monoclonal H23, kindly provided by J. Sanes
(Yamagata et al., 1995) and
mouse monoclonal mAb 12-I-4E-311 and rabbit polyclonal rb 4003, both kindly
provided by F. Rathjen (Chang et al.,
1990).
Binding and APP processing assays
Binding assays using fusion proteins were as described
(Flanagan and Cheng, 2000). AP
fusions were normalized for AP activity. Fc fusions were quantitated by
anti-Fc western with Li-COR Odyssey scanner. For
Fig. 5A, relative concentration
of Fc fusion proteins, as compared with contactin 3 FN-Fc, were: c3Ig1-4-Fc,
2.7; c3Ig5-6-Fc, 0.2; c3FN-Fc, 1; c4Ig1-4-Fc, 0.1; c4Ig5-6-Fc, 5.5; c4FN-Fc,
1.7. For Fig. 4A, Fc
concentrations were normalized.
For APP processing assays, 293T cells were transfected using TransIT-LT1 (Mirus Bio). After 1-2 days, plates were ice chilled, 5 minutes; lysed in 1% Triton X-100, 10 mM Tris pH 8.0, plus 140 mM NaCl, 20 minutes; and cleared lysates were combined with sample buffer. Western blots were probed with anti-HA (monoclonal 3F10, Roche), followed by HRP- or IRdye800-conjugated anti-rat antibody (Rockland).
RNAi experiments
Control virus contains EGFP-F (Clontech) in RCASBP(B) replication-competent
retrovirus. For contactin 4 shRNA virus, pGSU6-GFP (Genlantis) was used
according to manufacturer's instructions with target sequence
CTACGAGTGTGTCGCTGAA (Reynolds et al.,
2004), and the U6 promoter and shRNA sequence were inserted into
the control virus downstream of EGFP-F. Because we do not have an antibody to
chick contactin 4, knockdown was tested on tagged chick contactin 4-myc-His,
co-transfected with contactin 5-Fc control, APtag5 and shRNA or control
RCASBP(B) plasmid into 293T cells. Supernatants, normalized for transfection
by AP activity, were analyzed by western blot with IRdye800-conjugated
anti-myc and IRdye700DX-conjugated anti-human Fc. The shRNA construct,
compared with control virus, was confirmed to specifically knockdown protein
levels of contactin 4 (P<0.0001), and not the contactin 5 internal
control (see Fig. S1D in the supplementary material). For outgrowth assays,
stage 9-11 chick embryos were electroporated with RCASBP(B) plasmids as
described (Schulte et al.,
1999). Green fluorescence was used to select highly infected
(approximately 50-95%) retinas.
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Glass coverslips were first coated with 20 µg/ml
poly-L-lysine. Where multiple purified proteins (Fc fusions, 20
µg/ml; or laminin, 10 µg/ml, BD Biosciences) were used, they were mixed
to coat coverslips simultaneously. For purified proteins plus a supernatant
(AP fusion or mock), coating was first with purified proteins, then
supernatants. Axons were fluorescently labeled in 33 µM carboxyfluorescein
diacetate, succinimidyl ester (Invitrogen), 10 minutes. Since basal growth
varied between experiments, most figures show a single experiment, with
similar trends being observed in multiple experiments, except
Fig. 7K which shows three
experiments normalized to the average growth of control axons on
NgCAM+APPs.
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RESULTS |
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TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
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, for use as an
affinity probe (Flanagan and Cheng,
2000). We found that AP-APPs binds to embryonic chick
brain, with particularly prominent binding to the optic tectum
(Fig. 1B). Binding was also
seen in the olfactory bulb, as well as other regions
(Fig. 1B). Within the tectum,
the most prominent AP-APPs binding appeared to be localized to RGC
axons. The staining spread across the tectum with a developmental time course
similar to RGC axon ingrowth (Goldberg,
1974), appearing at the anterior end by Hamburger-Hamilton (HH)
stage 33 (E8.5 under our conditions), with some labeled axons reaching the
posterior tectum by HH 38 (E12.5), and covering the tectum by HH 41 (E15.5)
(Fig. 1D-F and data not shown).
The staining also had a prominently striated appearance that is characteristic
of axons (Fig. 1C).
Furthermore, in monocular chick embryos (one naturally occurring, two
surgically enucleated), AP-APPs binding was strongly reduced in the
tectal hemisphere contralateral to (and therefore normally innervated by) the
missing eye (Fig. 1G).
Two lines of evidence suggested that AP-APPs was detecting more than
one binding partner. First, a nested deletion analysis of APP identified two
regions that produced different binding patterns
(Fig. 2A). A middle domain
(amino acids 199-293) was sufficient for weak binding to RGC axons in the
tectum (Fig. 2C), whereas a
somewhat longer region (amino acids 199-345) gave stronger RGC binding
comparable to full-length AP-APPs
(Fig. 2B; binding pattern 1;
green bar in Fig. 2A), but both
gave little binding above background to the olfactory bulb
(Fig. 2B,C). By contrast, an
N-terminal domain of APP (amino acids 18-205) showed particularly strong
binding to the olfactory bulb, in addition to widespread binding above
background throughout the brain, including the tectum
(Fig. 2F; binding pattern 2;
blue bar in 2A). Second, treatment of brains with PI-PLC
(phosphatidylinositol-specific phospholipase C), which cleaves GPI anchorages,
greatly reduced AP-APPs binding to the olfactory bulb, whereas binding
to tecta appeared less affected (Fig.
2D,E), suggesting that the predominant APP binding partner
detected in olfactory bulbs is GPI-anchored, whereas the tectum appears to
contain a GPI-anchored binding partner and additional non-GPI-anchored
partner(s).
The APLP1 ectodomain, fused to an AP tag, was also tested for binding to embryonic chick brain. Binding was widespread, but particularly prominent in the olfactory bulb (Fig. 2G), similar to that observed for the APP N-terminal domain, suggesting that the N-terminal domains of APP and APLP1 might share binding partners (consistent with our subsequent molecular experiments).
APP binds specific contactins
We next developed a protocol to selectively purify extracellular binding
partners for APP from sites in developing brain with prominent APP binding.
Tecta were surface biotinylated, then incubated in one of three probes
(AP-APPs, AP-APP(199-345) or AP control), washed, incubated in DTSSP (a
cleavable, membrane-impermeable crosslinker) then lysed and immunoprecipitated
for the AP tag. Subsequent western blots for biotin revealed prominent bands
that co-immunoprecipitated with AP-APPs but not with AP alone
(Fig. 3A). AP-APP(199-345)
co-immunoprecipitated the same biotinylated bands, though to a lesser degree
(data not shown). Two prominent bands between 120 kDa and 150 kDa were seen in
repeated experiments (Fig. 3A,
asterisks). Additional, fainter bands at higher molecular weight were
sometimes seen.
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co-IP and
AP-APP(199-345) co-IP gels, so any proteins identified might interact with
AP-APP(199-345), AP-APPs, or both. Tandem mass spectrometry identified
human placental alkaline phosphatase and APP, both presumably derived from the
probe, and only one other protein, contactin 4, as a strong match to the
sample. Contactin 4 was also among the proteins we identified in an
independent approach involving purification and mass spectrometry of
GPI-anchored proteins in the olfactory bulb (data not shown).
These mass spectrometry studies suggested that contactin 4 binds APP.
However, interactions in the context of an intact cell or tissue can be
indirect or non-specific. To verify the interaction directly in a cell-free
system, we generated an Fc fusion of contactin 4 and assayed its binding to
AP-APPs. To measure affinity, binding curves were generated by varying
the concentration of AP fusion protein. To investigate specificity, we
similarly tested the remaining five contactins and another APP family protein,
APLP1 (Fig. 4). The results
revealed binding of APP to contactins 3 and 4. This fits with the homology
relationships, as contactins 3 and 4 are the most closely related pair within
the contactin family (Ogawa et al.,
1996). APLP1 bound contactins 3 and 4, and also contactin 5. No
saturable binding was detected in the other pairs tested, suggesting that if
there is an interaction, the affinity is low. The calculated dissociation
constant (KD) for APP and contactin 4 was 17 nM, whereas
other KDs ranged from 22 to 35 nM
(Fig. 4B-F).
To dissect which regions of the molecules were involved, deletion constructs were analyzed. In contactin 3 or 4, the fibronectin domains were found to be sufficient for binding. This is striking, as most other interactions of IgCAMs are mediated by the Ig-like domains. In APP, amino acids 18-205 were sufficient for binding (Fig. 5A,D). The localization of the binding domain to the N-terminal portion of APP, and the observation that contactins 3 and 4 are GPI-anchored proteins, are consistent with these proteins being partly or entirely responsible for what we termed `binding pattern 2' in embryonic chick brain (see Fig. 2).
APP interacts with NgCAM
Since our PI-PLC experiments (Fig.
2D,E) suggested the presence of at least one non-GPI-anchored APP
binding partner in tecta, we generated a list of further candidate APP binding
partners by identifying tectal cell-surface proteins of relevant molecular
weights. Chick tecta were surface labeled with biotin, biotinylated proteins
were purified and separated by SDS-PAGE, and bands corresponding to the
molecular weights of the biotinylated bands seen in
Fig. 3A were analyzed by tandem
mass spectrometry. The sequences of the identified proteins were analyzed for
transmembrane domains or signal peptides to confirm likely extracellular
expression. The candidate proteins identified in this way were CHL1, contactin
1, NCAM, neogenin, neurofascin, NgCAM, NrCAM, prominin-like 2 and
tenascin.
To test these candidate proteins for APP association, we performed a
crosslinker-based co-IP as in Fig.
3, then used antibodies against candidate proteins for western
blot detection. Of the antibodies tested (see Materials and methods), only
two, both directed against NgCAM, recognized bands in immunoprecipitates of
AP-APPs, but not of the AP control
(Fig. 5B). The primary band
detected by both NgCAM antibodies (Fig.
5B) appears to correspond well to the upper biotinylated band
marked in Fig. 3A. Additional
specific bands are also likely to be due to NgCAM; species of 80, 136, 190 and
210 kDa have been reported, with the predominant 80 and 136 kDa forms arising
by proteolysis (Burgoon et al.,
1991), and these are likely to correspond to the predominant bands
detected here (asterisks in Fig.
5B). Similar crosslinker-based affinity purifications using
AP-APP(199-345) as a probe revealed that NgCAM does co-precipitate with APP
amino acids 199-345 (Fig. 5C),
the domain which produces binding pattern 1
(Fig. 2).
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levels; Cao and Sudhof,
2004; Hass and Yankner,
2005). We therefore examined the effect of contactin 4 and NgCAM
on APP processing. In cells transfected with APP-HA, co-expression of
contactin 4- or NgCAM-fusion proteins resulted in increased levels of a small
HA-tagged fragment (Fig. 5E),
identified as APP CTF (C-terminal fragment ) by apparent
molecular weight (Fig. 5F). We
also saw increased levels of APP-HA, suggesting that contactin 4 and NgCAM can
enhance the stability or expression of full-length APP. The increase in
CTF might be secondary to the increase in full-length APP, but because
in some cases the increase in CTF appeared greater than the increase in
full-length APP, regulation of -site cleavage might also be involved.
Although co-transfection of soluble tagged forms of contactin 4 or NgCAM with
APP-HA generally increased CTF levels up to several fold, in a smaller
number of experiments, it resulted in an equally dramatic decrease in
CTF levels, often with an accompanying decrease in full-length APP.
Although we do not know the reason for these differing results, it might be
related to factors such as protein concentration or cellular state, which can
affect positive versus negative responses to other extracellular signaling
molecules (Song et al., 1998;
Hansen et al., 2004). In any
case, these experiments demonstrate that the presence of contactin 4 or NgCAM
can modulate CTF levels.
Expression in the visual system
For a binding interaction to have biological significance, the interacting
proteins should have in vivo expression patterns that allow them to interact.
Since APP binds prominently to retinal axons in the tectum
(Fig. 1), we assessed
expression of APP, contactins 3 and 4 and NgCAM in the retinotectal system by
in situ hybridization in E11.5 chick embryos. In the retina, all four genes
were expressed prominently in the RGC layer, which is the source of axons that
project to the tectum (Fig.
6A-E,K-N). Contactin 4 was also evident in other retinal layers.
In the tectum, all four genes were expressed in multiple layers, including
superficial layers through which RGC axons navigate
(Fig. 6F-J,O-R). APP protein
immunolocalization revealed prominent staining of the layers containing RGC
axons in the retina and tectum, as well as staining in other tectal layers
(Fig. 6S-Z). Along with
previous reports of NgCAM expression
(Lemmon and McLoon, 1986;
Stoker et al., 1995;
Yamagata et al., 1995;
Rager et al., 1996) and our
results showing that AP-APPs binds to RGC axons in the tectum
(Fig. 1), the expression
patterns indicate that these four proteins are suitably placed for
interactions involving axon-axon or axon-target contacts in the developing
retinotectal system.
Functional interactions in RGC axon outgrowth
Our analyses of binding interactions and expression patterns indicated that
APP, NgCAM and contactins might participate in retinal axon development, so we
next tested for functional effects on RGC axons. Retinal explants cultured on
NgCAM-Fc substrate showed substantial RGC axon outgrowth, as reported
previously (Doherty et al.,
1995; Morales et al.,
1996), whereas no outgrowth was seen on substrate coated with
AP-APPs or contactin 4-Fc (data not shown). Since APPs was
previously reported to promote neurite growth in other cell types
(Mattson, 1997), we tested
further and found that outgrowth on NgCAM was enhanced by either
AP-APPs (P=0.003) or AP-APP(18-205) (P=0.024)
(Fig. 7A-D). Similar results
were obtained by quantitating axon number
(Fig. 7D-F) or axon extension
(see Fig. S1A-C in the supplementary material). We next tested whether this
effect of APP is specific for NgCAM, as opposed to a more generalized effect
of APP, potentially unrelated to NgCAM. Our results showed that APPs
specifically promoted NgCAM-supported outgrowth, but not outgrowth on other
substrates such as laminin (Fig.
7E), demonstrating a specific functional interaction between APP
and NgCAM in regulating axon growth.
The observation that the N-terminal domain of APP, which binds contactins 3
and 4, was sufficient to potentiate NgCAM-dependent outgrowth, suggested a
model in which axonal contactin 3 or 4 acts as a receptor for APP. This model
predicts that soluble contactin 4 could act as a dominant-negative and block
signaling through axonally expressed contactin 3 or 4. We therefore tested
contactin 4-Fc, and found that it did indeed inhibit outgrowth, reducing
levels of outgrowth on AP-APPs plus NgCAM (P=0.011) to levels
seen on NgCAM alone (Fig. 7E).
Contactin 4-Fc also reduced growth on NgCAM alone, but, importantly, showed no
effect on laminin-dependent growth of RGC axons
(Fig. 7E,F), thereby
demonstrating specificity. We further tested the model by examining axon
outgrowth from retinas infected with virus expressing shRNA that targets
contactin 4. Explants expressing shRNA against contactin 4 exhibited less axon
growth than control explants, when grown on AP-APPs plus NgCAM
(P=0.021), whereas outgrowth on laminin was not significantly
affected (Fig. 7G-K). Thus,
data from two independent experimental approaches support a role for contactin
4 in the response by RGCs axons to NgCAM plus AP-APPs.
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DISCUSSION |
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TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
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Evidence for a ligand-receptor relationship can be provided by showing a
binding interaction, expression in suitable places to interact and a
functional interaction. In keeping with this, in addition to the binding
interaction demonstrated by our molecular studies, we find that all these
molecules are expressed in the developing retinotectal system, and that
APPs and contactin 4 can specifically modulate NgCAM-dependent axon
outgrowth, demonstrating functional interactions among these proteins that can
induce changes in cellular behavior.
Binding of APP family members to proteins of the contactin and L1CAM families
Our studies show that APP binds both contactin 3 and 4. APLP1 was found to
bind contactins 3 and 4, and also contactin 5. These results thus demonstrate
a set of promiscuous binding interactions between the APP and contactin
families, although binding was not seen in all pairwise combinations, thereby
indicating a degree of specificity. Although our functional studies have so
far focused on APP and contactin 4, it is likely that interaction among other
APP and contactin family members will also have functional consequences.
Binding of APP to contactins 3 and 4 is a direct interaction that can be
observed in a cell-free system. On contactin 4, the APP-binding site localizes
to the FN-like domains, which could leave the Ig domains of contactin free to
interact with other binding partners. On APP, the contactin-binding site is at
the N-terminus, involving amino acids 18-205. This corresponds essentially to
the E1 domain of APPs (Daigle and
Li, 1993), which has been implicated in many biological processes,
including neural stem cell proliferation
(Ohsawa et al., 1999),
synaptogenesis (Morimoto et al.,
1998) and neurite growth
(Small et al., 1994;
Ohsawa et al., 1997),
consistent with the possibility that interactions with contactins could be
involved in these biological processes.
|
), so our finding that APP interacts with contactin FN domains
could be consistent with simultaneous or cooperative binding in a multimeric
complex.
APP processing
APP cleavage can occur along two pathways. In the amyloidogenic pathway,
cleavage by β- and -secretases generates Aβ, implicated in
Alzheimer's disease. In the non-amyloidogenic pathway, cleavage by
-secretase precludes the formation of Aβ, suggesting the potential
to protect against Alzheimer's disease. The non-amyloidogenic pathway has also
been implicated in biological signaling because it generates the extracellular
APPs fragment that can regulate cell behavior when added to cell
cultures, and because -cleavage has been proposed to generate a signal
within the APP-bearing cell. We were therefore interested to find that
contactin 4 and NgCAM can alter the level of CTF, the C-terminal
-cleavage product, by several fold. Although we have not characterized
the specific mechanism (regulation of APP cleavage, stability, subcellular
localization, etc.), our experiments show effects on the level of CTF,
and any net change in the level of CTF is a biochemical signaling event
that may influence downstream pathways. Further studies would be required to
determine the biologically relevant signaling mechanisms, and whether the
interactions identified here could modulate Aβ production with
therapeutic relevance.
Functional interactions in regulating RGC axon growth
Further evidence for interactions among these proteins comes from our
functional studies of RGC axon outgrowth. APPs specifically potentiated
NgCAM-dependent, but not laminin-dependent, axon outgrowth, demonstrating a
specific functional interaction between APPs and NgCAM. Interfering
with contactin 4 by two independent methods, using a putative dominant
negative, or using shRNA against contactin 4, inhibited outgrowth on NgCAM and
APPs, but not on laminin, again demonstrating specific functional
interactions.
|
;
Flanagan, 2006). Indeed,
genetic studies have already shown that the mammalian NgCAM homolog, L1CAM, is
required for normal development of the retinotectal map
(Demyanenko and Maness, 2003).
In view of the interactions seen here, it will ultimately be interesting to
further test the roles of the L1CAM, APP and contactin families in vivo.
Since APPs and NgCAM stimulated RGC axon growth when presented
together in trans, and as they can interact physically, a likely model is that
they can function as a co-ligand complex, jointly interacting with and
activating a receptor. Since the domain of APP that interacts with contactin 4
is sufficient to promote axon growth, because both contactin 4-Fc and RNAi
against contactin 4 inhibited growth on NgCAM and APPs, and because
published studies have implicated contactin 2 as a co-receptor in
NgCAM-promoted neurite outgrowth
(Buchstaller et al., 1996), our
data support the model that axonal contactin 4 acts here by mediating a
response to molecules on the substratum. Taken together, our functional
studies of axon growth in vitro lead to a working model
(Fig. 7L) in which contactin 4
would act as an axonal receptor or co-receptor for an APPs-NgCAM
co-ligand complex. However, although our experiments clearly support
functional interactions among these proteins, further studies would be
required to investigate exactly which cis and trans interactions may occur in
a biological context.
APP has been widely proposed to function as both a receptor and a ligand.
In principle, these two functions could involve either the same or different
molecular interactions. Our results showing effects of contactin 4 and NgCAM
on APP processing could be consistent with a receptor function for APP.
Meanwhile, our studies of RGC axon outgrowth support a model in which
APPs and NgCAM can act together as ligands. These models are entirely
consistent, assuming formation of a complex that can have multiple signaling
outputs. Precedent for such a model comes from signaling complexes, such as
ephrins and Eph receptors, which can interact in cis and trans, and signal
bidirectionally (Kullander and Klein,
2002; Flanagan,
2006).
|
) reminiscent of the defects seen in patients with CRASH
syndrome, which is caused by mutations in L1CAM, the human homolog of NgCAM
(Fransen et al., 1995).
Overexpression of FASII in Drosophila results in an increased number
of neuromuscular synaptic boutons, which is dependent on downstream function
of the APP homolog APPL (Ashley et al.,
2005). FASII is the Drosophila homolog of NCAM, which is
distinct from, but closely related to, the Drosophila homologs of the
contactins (CONT) and the L1CAMs (Neuroglian)
(Vaughn and Bjorkman, 1996;
Hortsch, 2000;
Faivre-Sarrailh et al., 2004),
so these results might reflect an underlying evolutionary conservation of
interactions.
More generally, multiple studies implicate members of the APP, contactin
and L1CAM families in the development of neural connectivity in vertebrates.
APPs can affect neurite outgrowth, synaptogenesis, and synaptic
plasticity (Mattson, 1997;
Turner et al., 2003).
Contactins and L1CAMs have been extensively studied for their roles in neurite
outgrowth (Sonderegger, 1997;
Kamiguchi et al., 1998;
Falk et al., 2002), and
contactin 1 and L1CAM have been implicated in synapse formation or plasticity
(Hoffman, 1998;
Murai et al., 2002;
Saghatelyan et al., 2004).
A ligand for APP might also be expected to affect progression of
Alzheimer's disease, either by regulating functions of APP that control cell
behavior, or by modulating the processing of APP to Aβ. Consistent with
this, CNTN4 maps to chromosome 3p26, only 1.1 Mb from the D3S2387
marker, which was reported to have suggestive genetic linkage to Alzheimer's
disease (Blacker et al., 2003);
intriguingly, the only other identified genes as closely located to this
marker are CNTN6 (encoding contactin 6) and CHL1 (encoding
the L1CAM family protein, close homolog of L1). The work described here
identifies molecular and functional interactions of APP with contactin and
L1CAM family proteins, which might have general roles in neural development
and disease.
Supplementary material
Supplementary material for this article is available at
http://dev.biologists.org/cgi/content/full/135/6/1189/DC1
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ACKNOWLEDGMENTS |
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REFERENCES |
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TOP
SUMMARY
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
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