NCAM Is Essential for Axonal Growth and Fasciculation in the Hippocampus

doi:10.1006/mcne.1996.0588

Molecular and Cellular Neuroscience

Volume 8, Issue 5, 1997, Pages 323-335

https://doi.org/10.1006/mcne.1996.0588 Get rights and content

Abstract

The neural cell adhesion molecule (NCAM), probably the best characterized and most abundant cell adhesion molecule on neurons, is thought to be a major regulator of axonal growth and pathfinding. Here we present a detailed analysis of these processes in mice deficient for all NCAM isoforms, generated by gene targeting. The hippocampal mossy fiber tract shows prominent expression of polysialylated NCAM and the generation of new axonal projections throughout life. Focusing on this important intrahippocampal connection, we demonstrate that in the absence of NCAM, fasciculation and pathfinding of these axons are strongly affected. In addition we show alterations in the distribution of mossy fiber terminals. The phenotype is more severe in adult than in young animals, suggesting an essential role for NCAM in the maintenance of plasticity in the mature nervous system.

References (54)

W.M. Cowan et al.
The development of the dentate gyrus
Curr. Top. Dev. Biol.
(1980)
P. Doherty et al.
Neurite outgrowth in response to transfected NCAM changes during development and is modulated by polysialic acid
Neuron
(1990)
S.E. Fraser et al.
Alterations in theXenopusXenopus
Dev. Biol.
(1988)
P.A. Garrity et al.
Neuronal target recognition
Cell
(1995)
C. Goodman et al.
Developmental mechanisms that generate precise patterns of neuronal connectivity
Cell/Neuron (Suppl.)
(1993)
C. Goridis et al.
NCAM: Structural diversity, function and regulation of expression
Semin. Cell Biol.
(1992)
G. Grenningloh et al.
Pathway recognition by neuronal growth cones: Genetic analysis of neural cell adhesion molecules inDrosophila
Curr. Opinion Neurobiol.
(1992)
G. Grenningloh et al.
Genetic analysis of growth cone guidance inDrosophila.
Cell
(1991)
H. Hu et al.
The role of polysialic acid in migration of olfactory bulb interneuron precursors in the subventricular zone
Neuron
(1996)
R.O. Hynes et al.
Contact and adhesive specificities in the associations, migrations, and targeting of cells and axons
Cell
(1992)

L. Jamot et al.

Neuroanatomical divergence between two substrains of C57BL/6J inbred mice entails differential radial-maze learning

Brain Res.

(1994)

T.M. Jessell

Adhesion molecules and the hierarchy of neural development

Neuron

(1988)

L. Landmesser et al.

Distinct roles for adhesion molecules during innervation of embryonic chick muscle

Dev. Biol.

(1988)

D.M. Lin et al.

Genetic analysis of Fasciclin II inDrosophila:

Neuron

(1994)

D. Muller et al.

PSA-NCAM is required for activity induced synaptic plasticity

Neuron

(1996)

K. Ono et al.

N-CAM mutation inhibits tangential neuronal migration and is phenocopied by enzymatic removal of polysialic acid

Neuron

(1994)

A.F. Pimenta et al.

The limbic system-associated protein is an Ig superfamily member that mediates selective neuronal growth and axon targeting

Neuron

(1995)

U. Schuch et al.

Neural cell adhesion molecules influence second messenger systems

Neuron

(1989)

T. Seki et al.

Distribution and possible roles of the highly polysialylated neural cell adhesion molecule (NCAM-H) in the developing and adult central nervous system

Neurosci. Res.

(1993)

J. Silver et al.

Guidance of optic axons in vivo by a performed adhesive pathway on neuroepithelial endfeet

Dev. Biol.

(1984)

J. Tang et al.

Polysialic acid regulates growth cone behavior during sorting of motor axons in the plexus region

Neuron

(1994)

M. Tessier-Lavigne

Axon guidance by diffusible repellants and attractants

Curr. Opinion Genet. Dev.

(1994)

J.P. Thiery et al.

Adhesion among neural cells of the chicken embryo. II. Purification and characterisation of a cell adhesion molecule from chicken retina

J. Biol. Chem.

(1977)

H. Tomasiewicz et al.

Genetic deletion of a neural cell adhesion molecule variant (N-CAM-180) produces distinct defects in the central nervous system

Neuron

(1993)

K.W. Tosney et al.

The distribution of NCAM in the chick hindlimb during axon outgrowth and synaptogenesis

Dev. Biol.

(1986)

J.H.H.M. van Daal et al.

A genetic-correlation study of hippocampal structural variation and exploration activities in mice

Behav. Brain Res.

(1991)

Cited by (257)

Chemical and mechanical control of axon fasciculation and defasciculation
2023, Seminars in Cell and Developmental Biology
Neural networks are constructed through the development of robust axonal projections from individual neurons, which ultimately establish connections with their targets. In most animals, developing axons assemble in bundles to navigate collectively across various areas within the central nervous system or the periphery, before they separate from these bundles in order to find their specific targets. These processes, called fasciculation and defasciculation respectively, were thought for many years to be controlled chemically: while guidance cues may attract or repulse axonal growth cones, adhesion molecules expressed at the surface of axons mediate their fasciculation. Recently, an additional non-chemical parameter, the mechanical longitudinal tension of axons, turned out to play a role in axon fasciculation and defasciculation, through zippering and unzippering of axon shafts. In this review, we present an integrated view of the currently known chemical and mechanical control of axon:axon dynamic interactions. We highlight the facts that the decision to cross or not to cross another axon depends on a combination of chemical, mechanical and geometrical parameters, and that the decision to fasciculate/defasciculate through zippering/unzippering relies on the balance between axon:axon adhesion and their mechanical tension. Finally, we speculate about possible functional implications of zippering-dependent axon shaft fasciculation, in the collective migration of axons, and in the sorting of subpopulations of axons.
3D culture of the spinal cord with roots as an ex vivo model for comparative studies of motor and sensory nerve regeneration
2023, Experimental Neurology
Motor and sensory nerves exhibit tissue-specific structural and functional features. However, in vitro models designed to reflect tissue-specific differences between motor and sensory nerve regeneration have rarely been reported. Here, by embedding the spinal cord with roots (SCWR) in a 3D hydrogel environment, we compared the nerve regeneration processes between the ventral and dorsal roots. The 3D hydrogel environment induced an outward migration of neurons in the gray matter of the spinal cord, which allowed the long-term survival of motor neurons. Tuj1 immunofluorescence labeling confirmed the regeneration of neurites from both the ventral and dorsal roots. Next, we detected asymmetric ventral and dorsal root regeneration in response to nerve growth factor (NGF) and glial cell line–derived neurotrophic factor (GDNF), and we observed motor and sensory Schwann cell phenotypes in the regenerated ventral and dorsal roots, respectively. Moreover, based on the SCWR model, we identified a targeted effect of collagen VI on sensory nerve fasciculation and characterized the protein expression profiles correlating to motor/sensory-specific nerve regeneration. These results suggest that the SCWR model can serve as a valuable ex vivo model for comparative study of motor and sensory nerve regeneration and for pharmacodynamic evaluations.
Oxidized linoleic acid metabolites regulate neuronal morphogenesis in vitro
2023, Neurochemistry International
Linoleic acid (LA, 18:2n-6) is an essential nutrient for optimal infant growth and brain development. The effects of LA in the brain are thought to be mediated by oxygenated metabolites of LA known as oxidized LA metabolites (OXLAMs), but evidence is lacking to directly support this hypothesis. This study investigated whether OXLAMs modulate key neurodevelopmental processes including axon outgrowth, dendritic arborization, cell viability and synaptic connectivity. Primary cortical neuron-glia co-cultures from postnatal day 0–1 male and female rats were exposed for 48h to the following OXLAMs: 1) 13-hydroxyoctadecadienoic acid (13-HODE); 2) 9-hydroxyoctadecadienoic acid (9-HODE); 3) 9,10-dihydroxyoctadecenoic acid (9,10-DiHOME); 4) 12(13)-epoxyoctadecenoic acid (12(13)-EpOME); 5) 9,10,13-trihydroxyoctadecenoic acid (9,10,13-TriHOME); 6) 9-oxo-octadecadienoic acid (9-OxoODE); and 7) 12,13-dihydroxyoctadecenoic acid (12,13-DiHOME). Axonal outgrowth, evaluated by Tau-1 immunostaining, was increased by 9-HODE, but decreased by 12,13-DiHOME in male but not female neurons. Dendrite arborization, evaluated by MAP2B-eGFP expression, was affected by 9-HODE, 9-OxoODE, and 12(13)-EpOME in male neurons and, by 12(13)-EpOME in female neurons. Neither cell viability nor synaptic connectivity were significantly altered by OXLAMs. Overall, this study shows select OXLAMs modulate neuron morphology in a sex-dependent manner, with male neurons being more susceptible.
Periostin-expressing Schwann cells and endoneurial cardiac fibroblasts contribute to sympathetic nerve fasciculation after birth
2021, Journal of Molecular and Cellular Cardiology
Citation Excerpt :
To study whether the ICNS neurons fasciculate during the postnatal period, expression of the fasciculation and cell-cell adhesion marker PSA-NCAM was assessed in sympathetic, parasympathetic, and sensory nerves. PSA-NCAM has been used as a general marker of maturation but it has been also been demonstrated to be necessary for normal axon fasciculation [35,36]. Expression of PSA-NCAM in TH+ sympathetic nerves was detected from P0 to P7 (Fig. 4A), while, in ChAT+ parasympathetic nerves, the expression of PSA-NCAM was maintained from P0 to P30 (Fig. 4B).
The intracardiac nervous system (ICNS) is composed of neurons, in association with Schwann cells (SC) and endoneurial cardiac fibroblasts (ECF). Besides heart rhythm control, recent studies have implicated cardiac nerves in postnatal cardiac regeneration and cardiomyocyte size regulation, but cardiac SC and ECF remain understudied. During the postnatal period, the ICNS undergoes intense remodeling with nerve fasciculation and elongation throughout the myocardium, partially guided by the extracellular matrix (ECM). Here we report the origins, heterogeneity, and functions of SC and ECF that develop in proximity to neurons during postnatal ICNS maturation.
Periostin lineage (Postn+) cells include cardiac Remak SC and ECF during the postnatal period in mice. The developmental origins of cardiac SC and ECF were examined using Rosa26^eGFP reporter mice bred with Wnt1Cre, expressed in Neural crest (NC)-derived lineages, or tamoxifen-inducible Tcf21MerCreMer, expressed predominantly in epicardial-derived fibroblast lineages. ICNS components are NC-derived with the exceptions of the myelinating Plp1+ SC and the Tcf21+ lineage-derived intramural ventricular ECF. In addition, Postn+ lineage GFAP- Remak SC and ECF are present around the fasciculating cardiac nerves. Whole mount studies of the NC-derived cells confirmed postnatal maturation of the complex ICNS network from P0 to P30. Sympathetic, parasympathetic, and sensory neurons fasciculate from P0 to P7 indicated by co-staining with PSA-NCAM. Ablation of Postn+ cells from P0 to P6 or loss of Periostin leads to reduced fasciculation of cardiac sympathetic nerves. In addition, collagen remodeling surrounding maturing nerves of the postnatal heart is reduced in Postn-null mice.
Postn+ cells include cardiac SC and ECF during postnatal nerve maturation, and these cells have different embryonic origins. At P7, the Postn+ cells associated with cardiac nerves are mainly Remak SC and ECF. Ablation of the Postn+ cells from P0 to P6 and also loss of Postn in Postn-null mice leads to reduced fasciculation of cardiac nerves at P7.
Spatiotemporal processing of neural cell adhesion molecules 1 and 2 by BACE1 in vivo
2021, Journal of Biological Chemistry
Citation Excerpt :
Altogether, these results support the LC/MS/MS data showing that BACE1 cleaves NCAM1 at Glu 671 (between Y670 and E671) in vitro. NCAM1 germline knockout mice showed size reduction of the OB, deficits in spatial learning (Morris Water Maze) (57), and altered distribution of mossy fibers in the HC (58). NCAM2 knockout mice showed disrupted compartmental organization of axons and dendrites in olfactory glomeruli (59).
Neural cell adhesion molecules 1 (NCAM1) and 2 (NCAM2) belong to the cell adhesion molecules of the immunoglobulin superfamily and have been shown to regulate formation, maturation, and maintenance of synapses. NCAM1 and NCAM2 undergo proteolysis, but the identity of all the proteases involved and how proteolysis is used to regulate their functions are not known. We report here that NCAM1 and NCAM2 are BACE1 substrates in vivo. NCAM1 and NCAM2 overexpressed in HEK cells were both cleaved by metalloproteinases or BACE1, and NCAM2 was also processed by γ-secretase. We identified the BACE1 cleavage site of NCAM1 (at Glu 671) and NCAM2 (at Glu 663) using mass spectrometry and site-directed mutagenesis. Next, we assessed BACE1-mediated processing of NCAM1 and NCAM2 in the mouse brain during aging. NCAM1 and NCAM2 were cleaved in the olfactory bulb of BACE1+/+ but not BACE1−/− mice at postnatal day 10 (P10), 4 and 12 months of age. In the hippocampus, a BACE1-specific soluble fragment of NCAM1 (sNCAM1β) was only detected at P10. However, we observed an accumulation of full-length NCAM1 in hippocampal synaptosomes in 4-month-old BACE1−/− mice. We also found that polysialylated NCAM1 (PSA-NCAM1) levels were increased in BACE1−/− mice at P10 and demonstrated that BACE1 cleaves both NCAM1 and PSA-NCAM1 in vitro. In contrast, we did not find evidence for BACE1-dependent NCAM2 processing in the hippocampus at any age analyzed. In summary, our data demonstrate that BACE1 differentially processes NCAM1 and NCAM2 depending on the region of brain, subcellular localization, and age in vivo.
Decreased serum NCAM is positively correlated with hippocampal volumes and negatively correlated with positive symptoms in first-episode schizophrenia patients
2020, Journal of Psychiatric Research
Neural cell adhesion molecule (NCAM) plays an important role in neurodevelopmental processes and regulates hippocampal plasticity. This study investigated the relationship between the serum NCAM concentrations and hippocampal volume and psychotic symptoms in first-episode drug naïve schizophrenia (FES) patients.
Forty-four FES patients and forty-four healthy controls (HC) were recruited in this study. Serum concentrations of NCAM were measured by ELISA. Psychiatric symptoms were assessed by the positive and negative syndrome scale (PANSS). Brain structural images were obtained using a 3T MRI Scanner and obtained T1 images were processed in order to determine hippocampal grey matter volumes.
Schizophrenia patients revealed significantly decreased serum NCAM concentrations (p = 0.017), which were positively correlated with the left (r = 0.523, p < 0.001) and right (r = 0.449, p = 0.041) hippocampal volumes, but negatively correlated with the PANSS positive symptom scores (r = −0.522 p = 0.001). However, no such correlations existed in the HC group.
This is the first time to report that decreased serum NCAM concentrations were associated with hippocampal volumes and symptom severity in FES patients. Our data indicate that the low NCAM is possible neuropathology that is associated with the decreased hippocampus in FES patients.

View all citing articles on Scopus

^☆: G. Paxinos, Ed.

View full text

Regular ArticleNCAM Is Essential for Axonal Growth and Fasciculation in the Hippocampus☆

Abstract

Curr. Top. Dev. Biol.

Neuron

Dev. Biol.

Cell

Cell/Neuron (Suppl.)

Semin. Cell Biol.

Curr. Opinion Neurobiol.

Cell

Neuron

Cell

Brain Res.

Neuron

Dev. Biol.

Neuron

Neuron

Neuron

Neuron

Neuron

Neurosci. Res.

Dev. Biol.

Neuron

Curr. Opinion Genet. Dev.

J. Biol. Chem.

Neuron

Dev. Biol.

Behav. Brain Res.

Regular Article
NCAM Is Essential for Axonal Growth and Fasciculation in the Hippocampus☆