Fasciclin 2
FAS2 is the homolog of the vertebrate neural cell adhesion molecule (N-CAM). The Drosophila Neuroglian, also an Ig superfamily member, is a homolog of vertebrate LI. The fact that LI and N-CAM have maintained their identity through evolution, indicates the selective pressure for their function. It also indicates that there has to be an even more primitive CAM, ancestral to both LI and N-CAM (Bieber, 1989). The homology for FAS2 to N-CAM is only 20%, although the domain structure is conserved (Grenningloh, 1991).
A particularly dramatic example of directed
migration has been documented within the developing enteric
nervous system (ENS) of the moth Manduca sexta. During the
formation of the ENS, a population of approximately 300 post-mitotic
cells (the EP cells) delaminates from a neurogenic
placode to form a discrete packet of undifferentiated neurons
at the foregut-midgut boundary. The completion of their development is delayed,
however, until a new set of migratory pathways differentiates
on the adjacent midgut, where a set of visceral muscle bands
coalesce at eight specific locations around the midgut surface.
Once these pathways have formed, subsets of EP cells then
migrate rapidly onto each muscle band, traveling several
hundred mm over the course of 7-10 hours. Only after this migratory phase is complete
do the neurons form mature synaptic contacts and express transmitter phenotypes, a developmental sequence that is regulated in
part by the migratory process (Wright, 1999).
The insect cell adhesion receptor fasciclin II is expressed
by specific subsets of neural and non-neural cells during
embryogenesis and has been shown to control growth cone
motility and axonal fasciculation.
Probes specific for Manduca fasciclin II (MFas II)
show that while the EP cells express fasciclin II throughout
embryogenesis, their muscle band pathways express
fasciclin II only during the migratory period.
Manipulations of fasciclin II in embryonic culture using
blocking antibodies, recombinant fasciclin II fragments,
and enzymatic removal of glycosyl phosphatidylinositol-linked
fasciclin II produce concentration-dependent
reductions in the extent of EP cell migration. These results
support a novel role for fasciclin II, indicating that this
homophilic adhesion molecule is required for the
promotion or guidance of neuronal migration (Wright, 1999).
Still unresolved is the precise mechanism by which fasciclin
II-mediated interactions affect neuronal motility. The simplest
interpretation of the results presented in this paper is that the onset of MFas II
expression within the newly formed muscle bands establishes
a permissive substrate for the EP cells on the midgut, so that
MFas II-mediated homophilic interactions between the
neurons and the muscle bands lead to their migration along
these pathways. This hypothesis is supported by observations that show that the muscle bands are both necessary and
sufficient for neuronal migration, because the EP cells will not
migrate onto the midgut musculature unless they are in direct
contact with one of the muscle bands.
Moreover, neither the application of anti-MFas II antibodies
nor recombinant MFas II fragments results in a general
dissociation of the premigratory packet of EP cells; rather,
these treatments appear to interfere specifically with the
formation of homophilic interactions between the neurons and
the newly formed muscle bands. However, manipulations
of MFas II in culture also perturb the coalescence of the
muscle bands themselves, suggesting that fasciclin
II may play a role in the differentiation of the bands from the
visceral mesoderm. Although
the EP cells will migrate in culture onto the muscle band cells even when
the bands have not completely coalesced, it
is possible that the experimental manipulations of MFas II affect
migration indirectly by preventing the normal differentiation of
their migratory pathways. Although the data support a role for MFas
II in guiding the EP cells along the muscle bands once these
pathways have formed, an additional process must stimulate
the preferential release of fasciclin II-dependent adhesive
interactions within the premigratory cluster in order for
migration to occur. Following the migratory period, the fibers continue to
extend axonal processes along the same muscle band pathways
on the midgut. Intriguingly, this behavioral transition from
migration to axon outgrowth coincides with the disappearance
of MFas II expression from the muscle bands, although MFas
II levels within the axons of the EP cells remain high. It is possible that the
termination of fasciclin II expression in the muscle bands
precludes further migration by the neurons, while other
guidance cues associated with the muscle bands (such as
neuroglian) continue to support axonal outgrowth (Wright, 1999).
Neuorfascin, a member of the L1 family of ankyrin-binding cell adhesion molecules, is a substrate for
protein tyrosine kinase(s) and phosphatase(s); it identifies the highly conserved FIGQY tyrosine in the cytoplasmic domain
as the principal site of phosphorylation, and demonstrates that phosphorylation of the FIGQY tyrosine abolishes ankyrin-binding activity. Neurofascin expressed in neuroblastoma cells is subject to tyrosine phosphorylation after activation of tyrosine kinases by NGF or bFGF or inactivation of tyrosine phosphatases with vanadate or dephostatin. Furthermore, both neurofascin and the related molecule Nr-CAM are tyrosine phosphorylated in a developmentally regulated pattern in rat brain. The FIGQY sequence is present in the cytoplasmic domains of all members of the L1 family of neural cell adhesion molecules. Phosphorylation of the FIGQY tyrosine abolishes ankyrin binding, as determined by coimmunoprecipitation of endogenous ankyrin and in vitro ankyrin-binding assays. Measurements of fluorescence recovery after photobleaching demonstrate that phosphorylation of the FIGQY tyrosine also increases lateral mobility of neurofascin expressed in neuroblastoma cells to the same extent as removal of the cytoplasmic domain. Ankyrin binding, therefore, appears to regulate the dynamic behavior of neurofascin and is the target for regulation by tyrosine phosphorylation in response to external signals. These findings suggest that tyrosine phosphorylation at the FIGQY site represents a highly conserved mechanism, used by the entire class of L1-related cell adhesion molecules, for regulation of ankyrin-dependent connections to the spectrin skeleton (Garver, 1997).
During development of the primary olfactory projection, olfactory receptor axons must sort by odor specificity and seek
particular sites in the brain in which to create odor-specific glomeruli. In the moth Manduca sexta, Fasciclin II, a cell adhesion molecule in the immunoglobulin superfamily, is expressed by the axons of a subset of
olfactory receptor neurons during development and, in a specialized glia-rich 'sorting zone,' these axons segregate from
non-Fasciclin II-expressing axons before entering the neuropil of the glomerular layer. The segregation into Fasciclin
II-positive fascicles is dependent on the presence of the glial cells in the sorting zone. The expression patterns for different isoforms of Manduca Fasciclin II in the developing olfactory system has been explored. Olfactory receptor axons express transmembrane Fasciclin II during the period of axonal ingrowth and glomerulus development. Fascicles of
TM-Fasciclin II+ axons target certain glomeruli and avoid others, such as the sexually dimorphic glomeruli. These results
suggest that TM-Fasciclin II may play a role in the sorting and guidance of the axons. GPI-linked forms of Fasciclin II are expressed weakly by glial cells associated with the receptor axons before they reach the sorting zone, but not by sorting-zone glia. GPI-Fasciclin II may, therefore, be involved in axon-glia interactions related to stabilization of axons in the nerve, but probably not related to sorting (Higgins, 2002).
These results led to the hypothesis that the two isoforms
of Fas II have distinct functions in formation of the
olfactory pathway in Manduca. In the developing olfactory
system, just as was seen in the developing embryonic
enteric system, GPI-Fas II may serve an adhesive function
between cells of the perineurial sheath. In the olfactory
system, it may also play a role in axon-glia interactions in
the antennal nerve. That role is unlikely to be essential to
growth, since the glia that express GPI-linked Fas II
migrate into the antennal nerve from the antenna after
many olfactory receptor axons have already reached their
target glomeruli; perhaps GPI-Fas II participates in some sort of glial stabilization of the axons in the nerve. TM-Fas II, found almost exclusively on olfactory axons that extend from antennal nerve rootlets to
target glomeruli, probably serves a guidance function by
allowing axons destined to terminate in a subset of 14-21
glomeruli to recognize and fasciculate with each other. The
first axons to navigate a path to each incipient glomerulus
site presumably would use other cues to find those sites.
Subsequent axons would use Fas II and other adhesion molecules, in various combinations, to assort into molecularly specified fascicles specific for the 63 individual glomeruli that they form (Higgins, 2002).
The L1 family of cell adhesion molecules is predominantly expressed in the
nervous system. Mutations in human L1 cause neuronal diseases such as HSAS,
MASA, and SPG1. sax-7 gene encodes an L1 homologue in
Caenorhabditis elegans. In sax-7 mutants, the organization of ganglia and
positioning of neurons are abnormal in the adult stage, but these abnormalities
are not observed in early larval stage. Misplacement of neurons in sax-7 mutants
is triggered by mechanical force linked to body movement. Short and long forms
of SAX-7 exhibited strong and weak homophilic adhesion activities in in vitro
aggregation assay, respectively, which correlates with their different
activities in vivo. SAX-7 is localized on plasma membranes of neurons in vivo.
Expression of SAX-7 only in a single neuron in sax-7 mutants cell-autonomously
restores the neuron's
normal neuronal position. Expression of SAX-7 in two different head
neurons in sax-7 mutants leads to the forced attachment of these neurons. It is
proposed that both homophilic and heterophilic interactions of SAX-7 are
essential for maintenance of neuronal positions in organized ganglia (Sasakura, 2005 ).
A single immunoglobulin-like domain of the human neural cell
adhesion molecule L1 supports adhesion by multiple vascular and
platelet integrins (see Drosophila Myospheroid). The L1 has been shown to function as a homophilic ligand in a variety of
dynamic neurological processes. The sixth immunoglobulin-like domain of
human L1 (L1-Ig6) can function as a heterophilic ligand for multiple members of the integrin
superfamily, including alphavbeta3, alphavbeta1, alpha5beta1, and alphaIIbbeta3. The interaction
between L1-Ig6 and alphaIIbbeta3 is found to support the rapid attachment of activated human
platelets, whereas a corresponding interaction with alphavbeta3 and alphavbeta1 supports the
adhesion of umbilical vein endothelial cells. Mutation of the single Arg-Gly-Asp (RGD) motif in human
L1-Ig6 effectively abrogates binding by the aforementioned integrins. An L1 peptide containing this
RGD motif and corresponding flanking amino acids (PSITWRGDGRDLQEL) effectively blocks L1
integrin interactions and, as an immobilized ligand, supports adhesion via alphavbeta3, alphavbeta1,
alpha5beta1, and alphaIIbbeta3. Whereas beta3 integrin binding to L1-Ig6 is evident in the presence
of either Ca2+, Mg2+, or Mn2+, a corresponding interaction with the beta1 integrins is only observed
in the presence of Mn2+. Furthermore, such Mn2+-dependent binding by alpha5beta1 and alphavbeta1
is significantly inhibited by exogenous Ca2+. These findings suggest that physiological levels of calcium
will impose a hierarchy of integrin binding to L1 such that alphavbeta3 or active alphaIIbbeta3 >
alphavbeta1 > alpha5beta1. Given that L1 can interact with multiple vascular or platelet integrins it is
significant that de novo L1 expression on blood vessels is associated with
certain neoplastic or inflammatory diseases. Together these findings suggest an expanded and novel
role for L1 in vascular and thrombogenic processes (Felding-Habermann, 1997).
Mutations in the L1 gene induce a spectrum of human neurological disorders due to abnormal development of several brain structures and fiber tracts. Among its binding partners, L1 immunoglobulin superfamily adhesion molecule (Ig CAM) associates with neuropilin-1 (NP-1) to form a semaphorin3A (Sema3A) receptor and soluble L1 converts Sema3A-induced axonal repulsion into attraction. Using L1 constructs containing missense pathological mutations, it has been shown that this reversion is initiated by a specific trans binding of L1 to NP-1, but not to L1 or other Ig CAMs. This binding leads to activation of the NO/cGMP pathway. The L1-NP-1-binding site has been identified in a restricted sequence of L1 Ig domain 1, since a peptide derived from this region could reverse Sema3A repulsive effects. A pathological L1 missense mutation located in this sequence specifically disrupts both L1-NP-1 complex formation and Sema3A reversion, suggesting that the cross-talk between L1 and Sema3A might participate in human brain development (Castellani, 2002).
Intercellular communication involves either direct cell-cell contact or release and uptake of diffusible signals, two strategies mediated by distinct and largely nonoverlapping sets of molecules. The neural cell adhesion molecule NCAM can function as a signaling receptor for members of the glial cell line-derived neurotrophic factor (GDNF) ligand family. Association of NCAM with GFRalph1, a GPI-anchored receptor for GDNF, downregulates NCAM-mediated cell adhesion and promotes high-affinity binding of GDNF to p140NCAM, resulting in rapid activation of cytoplasmic protein tyrosine kinases Fyn and FAK in cells lacking RET, a known GDNF signaling receptor. GDNF stimulates Schwann cell migration and axonal growth in hippocampal and cortical neurons via binding to NCAM and activation of Fyn, but independently of RET. These results uncover an unexpected intersection between short- and long-range mechanisms of intercellular communication and reveal a pathway for GDNF signaling that does not require the RET receptor (Paratcha, 2003).
The neural cell adhesion molecule (N-CAM) is a homophilic cell adhesion protein that influences neurite outgrowth. A model for N-CAM homophilic binding has been proposed in which the Ig domains bind in a
pairwise antiparallel manner such that Ig I binds Ig V, Ig II binds Ig IV, and Ig III binds Ig III.
Astrocyte proliferation induced by growth factors such as basic fibroblast growth factor (bFGF) is inhibited by N-CAM. This inhibition is partially reversed by the glucocorticoid antagonist RU-486, suggesting that N-CAM signaling might activate the glucocorticoid receptor. Signaling after N-CAM binding in neurons has been examined in neurite outgrowth assays. It has been proposed that N-CAM signaling occurs through the cis
interaction of N-CAM with the FGF receptor and intracellular pathways stimulated by the FGF
receptor. It is therefore important to assess whether signaling after N-CAM binding involves
both the glucocorticoid receptor and FGF receptor pathways or whether there may be different pathways involved, depending on cell type or specific cellular events (Krushel,1998).
N-CAM inhibits astrocyte proliferation in vitro and in vivo, and
this effect is partially reversed by the glucocorticoid antagonist RU-486. The present studies have
tested the hypothesis that N-CAM-mediated inhibition of astrocyte proliferation is caused by homophilic
binding and involves the activation of glucocorticoid receptors. It was observed that all N-CAM Ig
domains inhibit astrocyte proliferation in parallel with their ability to influence N-CAM binding. At an intermediate concentration of the Ig domains there is a distinct difference in the ability of Ig domain fragments to inhibit proliferation. The
proliferation of other N-CAM-expressing cells also is inhibited by the addition of affinity chromatography purified N-CAM. In
contrast, the proliferation of astrocytes from knockout mice lacking N-CAM is not inhibited by added
N-CAM. These findings support the hypothesis that it is binding of soluble N-CAM to N-CAM on the
astrocyte surface that leads to decreased proliferation. Signaling pathways stimulated by growth
factors include activation of mitogen-activated protein (MAP) kinase. Addition of N-CAM inhibits
MAP kinase activity induced by basic fibroblast growth factor in astrocytes. In accord with previous
findings, that RU-486 can partially prevent the proliferative effects of N-CAM, inhibition of MAP
kinase activity by N-CAM is reversed by RU-486. MAP kinase activity in astrocytes is increased over 4-fold after bFGF treatment. However, when N-CAM is added simultaneously with bFGF, MAP kinase activity is reduced to 46% of the
value stimulated by bFGF alone. This inhibitory effect on MAP kinase activity is completely reversed if the
glucocorticoid antagonist RU486 is included with bFGF and N-CAM. The addition of N-CAM alone produces a small,
but reproducible, decrease in basal MAP kinase activity, whereas the addition of RU486 alone has little or no effect. These
results suggest that soluble N-CAM inhibits growth factor-induced MAP kinase activity and that this inhibition requires
activation of the glucocorticoid receptor (Krushel, 1998).
The ability of N-CAM to promote neurite outgrowth in neurons has been
postulated to occur through cis binding of N-CAM to a segment of the FGF receptor called the CAM homology domain. This conclusion was based on the observation that the presence of a 20-aa synthetic peptide corresponding to this domain could inhibit N-CAM-dependent neurite outgrowth. Proliferation stimulated by bFGF in astrocytes is reduced in the presence of N-CAM. The effects of the FGF receptor peptide was tested on the ability of N-CAM to affect astrocyte proliferation. Inclusion of N-CAM with either the FGF receptor peptide or a control peptide with the same amino acids in a random order reduces the amount of [3H]thymidine incorporation to levels equivalent to those of N-CAM alone, although addition of either peptide alone results in a slight decrease in proliferation. These results suggest that the ability of N-CAM to inhibit astrocyte proliferation is not likely to occur through direct interactions of N-CAM with the FGF receptor. Together, these findings indicate that homophilic N-CAM binding leads to inhibition of astrocyte proliferation via a pathway involving the glucocorticoid receptor and that the ability of N-CAM to influence astrocyte proliferation and neurite outgrowth involves different signal pathways (Krushel, 1998).
To examine the neural function of Csk (C-terminal Src kinase), a membrane-targeted form of Csk
(Src/Csk) and its kinase-defective variant (DK-Src/Csk) were both expressed in the embryonic carcinoma cell
line P19. Expression of Src/Csk, but not DK-Src/Csk, causes reduction of the specific activities of Src
and Fyn in the differentiated P19 cells. During neural differentiation, the specific activity of Src is
elevated in the control P19 cells, whereas the activation is completely eliminated in the Src/Csk
transfectant. In normally differentiated P19 cells, cross-linking of a cell adhesion molecule, L1, induces a
short-term activation of Src and Fyn. In the Src/Csk transfectant, L1 stimulation induces delayed
activation of Src and Fyn peaking at much lower levels than in the control cells. Src/Csk transfectants
develop normally in the initial stages of neural differentiation, but exhibit an apparent defect in
cell-to-cell interaction (neurite fasciculation and aggregation of cell bodies) in the later stages. These
findings imply that Csk is involved in the regulation of Src family kinases that play roles in cell-to-cell
interaction mediated by cell adhesion molecules (Takayama, 1997).
Axonal growth cones respond to adhesion molecules and to extracellular matrix components by rapid
morphological changes and growth rate modification. Neurite outgrowth mediated by the neural cell
adhesion molecule (NCAM) requires the src family tyrosine kinase p59(fyn) in nerve growth cones, but
the molecular basis for this interaction has not been defined. The NCAM140 isoform, which is found in
migrating growth cones, selectively co-immunoprecipitates with p59(fyn) from nonionic detergent extracts of early postnatal mouse cerebellum and transfected rat B35 neuroblastoma and COS-7 cells.
Whereas p59(fyn) is constitutively associated with NCAM140, the focal
adhesion kinase p125(fak), a nonreceptor tyrosine kinase known to mediate integrin-dependent signaling,
becomes recruited to the NCAM140-p59(fyn) complex when cells are reacted with antibodies against the
extracellular region of NCAM. Treatment of cells with a soluble NCAM fusion protein or with NCAM
antibodies causes a rapid and transient increase in tyrosine phosphorylation of p125(fak) and p59(fyn).
These results suggest that NCAM140 binding interactions at the cell surface induce the assembly of a
molecular complex of NCAM140, p125(fak), and p59(fyn) and activate the catalytic function of these
tyrosine kinases, initiating a signaling cascade that may modulate growth cone migration (Beggs, 1997).
The cell adhesion molecules (CAMs) NCAM, N-cadherin (see Drosophila Cadherin-N), and L1 are homophilic binding molecules that
stimulate axonal growth. It has been postulated that the above CAMs can stimulate axonal growth by
activating the fibroblast growth factor receptor (FGFR) in neurons (See Drosophila Breathless). Activation of NCAM and L1 can lead to phosphorylation of the FGFR. Both this and the neurite
outgrowth response stimulated by all three of the above CAMs are lost when a kinase-deleted, dominant
negative form of FGFR1 is expressed in PC12 cells. Transgenic mice have been generated that
express the dominant negative FGFR under control of the neuron-specific enolase (NSE) promoter. Cerebellar neurons isolated from these mice have also lost their ability to respond to NCAM,
N-cadherin, and L1. A peptide inhibitor of phospholipase C gamma (PLCgamma) that inhibits neurite
outgrowth stimulated by FGF also inhibits neurite outgrowth stimulated by the CAMs. It is
concluded that activation of the FGFR is both necessary and sufficient to account for the ability of the
above CAMs to stimulate axonal growth, and that PLCgamma is a key downstream effector of this
response (Saffell, 1997).
L1 is a neural cell adhesion molecule that has been shown to help guide nascent axons to their targets.
This guidance is based on specific interactions of L1 with its binding partners and is likely to involve
signaling cascades that alter cytoskeletal elements in response to these binding events. The phosphorylation of L1 and the role it may have in L1-directed neurite outgrowth has been examined. The phosphorylation site has been determined to be Ser1152. The L1 kinase activity from PC12 cells that phosphorylates this site
co-elutes with the S6 kinase, p90(rsk). Moreover, S6 kinase activity and p90(rsk) immunoreactivity
co-immunoprecipitate with L1 from brain. The phosphorylation site is located in a region of
high conservation between mammalian L1 sequences as well as L1-related molecules in vertebrates from
fish to birds. Neurons were loaded with peptides that encompass the phosphorylation site, as well as the flanking
regions, and their effects on neurite outgrowth were observed. The peptides, which include Ser1152,
inhibit neurite outgrowth on L1 but not on a control substrate, laminin. These data
demonstrate that the membrane-proximal 15 amino acids of the cytoplasmic domain of L1 are important
for neurite outgrowth on L1, and the interactions it mediates may be regulated by phosphorylation of
Ser1152 (Wong, 1996a).
Casein
kinase II (CKII), a ubiquitous serine/threonine kinase enriched in brain is able to phosphorylate
recombinant L1 cytoplasmic domain (L1CD), which consists of residues 1,144-1,257. CKII is able to phosphorylate a peptide encompassing amino acids
1,173-1,185, as well as a related peptide representing an alternatively spliced nonneuronal L1 isoform that
lacks amino acids 1,177-1,180. Serine to alanine
substitutions in these peptides indicate that the CKII phosphorylation site is at Ser1,181. When L1 immunoprecipitates are used to
phosphorylate L1CD, one of the residues phosphorylated is the same residue phosphorylated by CKII. Ser1,181 is found to be phosphorylated in newborn rat brain. These data
show that CKII is associated with and able to phosphorylate L1. This phosphorylation may be important
in regulating certain aspects of L1 function, such as adhesivity or signal transduction (Wong, 1996b).
Cell-cell interactions mediated via cell adhesion molecules (CAMs) are dynamically regulated during
nervous system development. One mechanism to control the amount of cell surface CAMs is to
regulate their recycling from the plasma membrane. The L1 subfamily of CAMs has a highly
conserved cytoplasmic domain that contains a tyrosine, followed by the alternatively spliced RSLE
(Arg-Ser-Leu-Glu) sequence. The resulting sequence of YRSL conforms to a tyrosine-based sorting
signal that mediates the clathrin-dependent endocytosis of signal-bearing proteins. L1 associates in rat brain with AP-2, a clathrin adaptor that captures plasma membrane proteins
that contain tyrosine-containing motifs, thus aiding endocytosis of these proteins by coated pits. In vitro assays demonstrate that this
interaction occurs via the YRSL sequence of L1 and the mu 2 chain of AP-2. In L1-transfected 3T3
cells, L1 endocytosis is blocked by dominant-negative dynamin that specifically disrupts
clathrin-mediated internalization. Furthermore, endocytosed L1 colocalizes with the transferrin receptor
(TfR), a marker for clathrin-mediated internalization. Mutant forms of L1 that lack the YRSL do not
colocalize with TfR, indicating that the YRSL mediates endocytosis of L1. In neurons, L1 is
endocytosed preferentially at the rear of axonal growth cones, colocalizing with Eps15, another marker
for the clathrin endocytic pathway. These results establish a mechanism by which L1 can be
internalized from the cell surface and suggest that an active region of L1 endocytosis at the rear of
growth cones is important in L1-dependent axon growth (Kamiguchi, 1998b).
To identify neuronal cell surface glycoproteins in the
Drosophila embryo,
antisera against horseradish peroxidase (HRP) was used to recognize a carbohydrate epitope that is selectively
expressed in the insect nervous system. A large number of neuronal glycoproteins (denoted "HRP proteins") apparently bear the HRP carbohydrate epitope. Polyclonal anti-HRP
antibodies were used to purify these proteins from Drosophila embryos. Three major HRP proteins are Neurotactin, Fasciclin I, and
an R-PTP, DPTP69D. Western blotting data suggest that Fasciclin II, Neuroglian, DPTP10D, and
DPTP99A are also HRP proteins (Desai, 1994).
LeechCAM is an
NCAM/FasII/ApCAM homolog, whereas Tractin, another Ig superfamily member, is a cleaved protein with several
unique features, including a PG/YG repeat domain that may be part of or interact
with the extracellular matrix. Tractin and LeechCAM are widely expressed neural
proteins that are differentially glycosylated in sets and subsets of peripheral sensory
neurons. These neurons form specific fascicles in the central nervous system. In vivo antibody
perturbation of the Lan3-2 glycoepitope demonstrates that it can selectively regulate
extension of neurites and filopodia. It is thought that local interactions involving the Lan3-2 epitope may be regulating defasciculation of sensillar neurons and facilitating the segregation of the axons into specific tracts. Thus, these experiments provide evidence that
differential glycosylation can confer functional diversity and specificity to widely
expressed neural proteins. The interaction between surface oligosaccharides and carbohydrate binding proteins could mediate pathfinding aspects of axonogenesis (Huang, 1997).
The mossy fiber axons of both the developing and adult dentate gyrus express the highly polysialylated form of neural cell adhesion molecule (NCAM) as they innervate the proximal apical dendrites of pyramidal cells in the CA3 region of the hippocampus. The present study used polysialic acid (PSA)-deficient and NCAM mutant mice to evaluate the role of PSA in mossy fiber development. The results indicate that removal of PSA by either specific enzymatic degradation or mutation of the NCAM-180 isoform that carries PSA in the brain causes an aberrant and persistent innervation of the pyramidal cell layer by mossy fibers, including excessive collateral sprouting and/or defasciculation of these processes, as well as formation of ectopic mossy fiber synaptic boutons. These results are considered in terms of two possible effects of PSA removal: an increase in the number of mossy fibers that can grow into the pyramidal cell layer and an inhibition of process retraction by formation of stable junctions including synapses. Because these defects on granule cells in the adult animal and PSA-positive granule cells continue to be produced in the mature brain, the present findings may be relevant to previous studies suggesting that PSA-NCAM function is required for long-term potentiation, long-term depression, and learning behaviors associated with hippocampus (Seki, 1998).
Sensory afferents in the leech are labeled with both constitutive and developmentally regulated glycosylations (markers) of their cell adhesion molecules (CAMs).
A constitutive mannose marker borne by these cells, recognized by Lan3-2 monoclonal antibody (mAb), mediates the formation of diffuse central arbors in these neurons. At the
ultrastructural level, the arbors consist of large, loosely organized axons rich with filopodia and synaptic vesicles. Perturbing the mannose-specific adhesion of this
first targeting step leads to a gain in cell-cell contact but a loss of filopodia and synaptic vesicles. During the second targeting step, galactose markers divide afferents
into different subsets. A subset is labeled by the marker recognized by Laz2-369 mAb. Initially, the galactose marker appears where afferents contact
central neurons. Subsequently it spreads proximally and distally, covering the entire afferent surface. Afferents now gain cell-cell contact, with central neurons and
self-similar afferents, but lose filopodia and synaptic vesicles. Extant synaptic vesicles prevail where afferents are apposed to central neurons. These neurons develop
postsynaptic densities and en passant synapses are formed. Perturbing the galactose-specific adhesion of this second targeting step causes a loss of cell-cell contact
but a gain in filopodia and synaptic vesicles, essentially returning afferents to the first targeting step. The transformation of afferent growth, progressing from mannose-
to galactose-specific adhesion, is consistent with a change from cell-matrix to cell-cell adhesion. By performing opposing functions in a temporal sequence,
constitutive and developmentally regulated glycosylations of CAMs collaborate in the synaptogenesis of afferents and the consolidation of self-similar afferents (Tai, 1999).
Fasciclin 2 Evolutionary homologs: Continued part 2/3 | part 3/3
Home page: The Interactive Fly © 1995, 1996 Thomas B. Brody, Ph.D.
The Interactive Fly resides on the
Fasciclin 2:
Biological Overview
| Regulation
| Developmental Biology
| Effects of Mutation
| References
Society for Developmental Biology's Web server.