Transfected F3/F11 neuronal cell surface protein mediates intercellular adhesion and promotes neurite outgrowth

doi:10.1016/0896-6273(91)90062-5

Neuron

Volume 6, Issue 4, April 1991, Pages 595-606

https://doi.org/10.1016/0896-6273(91)90062-5 Get rights and content

Abstract

The mouse neuronal F3 glycoprotein and its chicken homolog F11 belong to a subclass of proteins of the immunoglobulin superfamily with preferential localization on axons and neurites. We have transfected F3 cDNA into CHO cells. Biochemical analysis establishes that the cDNA we have cloned codes for a 130 kd phosphatidylinositol-anchored polypeptide. F3-expressing transfectants exhibited enhanced self-adhesive properties, aggregating with faster kinetics and forming larger aggregates than F3-negative control cells. When used as a culture substrate for sensory neurons, F3-transfected cells showed a markedly enhanced ability to promote neurite outgrowth compared with nontransfected cells. The results support the idea that F3/F11 and other closely similar proteins function as cell adhesion molecules that play a role in axonal growth and guidance.

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Among immunoglobulin domains, Ig2 and Ig3 are in charge of adhesive characteristics of Contactins [23]. Contactins interact with different known ligands, including itself, [25], the adhesion molecules Nr-CAM, Ng-CAM, and neurofascin [26–28], tenascin [29,30]), and PTPR [17–21,31,32]. The members of Protein Tyrosine Phosphatase Receptor (PTPR) family are integral cell-surface proteins, which regulate the intracellular tyrosine phosphorylation activities.
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Accordingly, NCAM expression was modified by learning and LTP in a time-dependent way in order to allow the processes of destabilization, remodelling and new stabilization of synapses (Schuster et al., 1998; Merino et al., 2000; Venero et al., 2006). Among the neural CAMs, we have recently been focusing on F3/Contactin, also known as Contactin-1, a glycoprotein belonging to the IgSF, involved in neuronal development, synaptic maintenance and in the organization of neuronal networks (Gennarini et al., 1991; Pesheva et al., 1993; Berglund et al., 1999; Murai et al., 2002; Bizzoca et al., 2003; Hu et al., 2003; Bizzoca et al., 2012). F3/Contactin has an ubiquitous role across species in development, being highly conserved in vertebrates, e.g. mouse, chicken, cow, humans (Gennarini et al., 1989a, 1989b, Furley et al., 1990; Ranscht, 1988; Berglund et al., 1994; Watanabe et al., 1995; Haenisch et al., 2005; Schweitzer et al., 2007) as well as invertebrates, such as Drosophila or Helix pomatia (Faivre-Sarrailh et al., 2004, Banerjee et al., 2006; Milanese et al., 2008).
Cell adhesion molecules (CAMs) have a pivotal role in building and maintaining synaptic structures during brain development participating in axonal elongation and pathfinding, glial guidance of neuronal migration, as well as myelination. CAMs expression persists in the adult brain particularly in structures undergoing postnatal neurogenesis and involved in synaptic plasticity and memory as the hippocampus. Among the neural CAMs, we have recently focused on F3/Contactin, a glycosylphosphatidyl inositol-anchored glycoprotein belonging to the immunoglobulin superfamily, involved in neuronal development, synaptic maintenance and organization of neuronal networks. Here, we discuss our recent data suggesting that F3/Contactin exerts a role in hippocampal synaptic plasticity and memory in adult and aged mice. In particular, we have studied long-term potentiation (LTP), spatial and object recognition memory, and phosphorylation of the transcription factor cAMP-Responsive-Element Binding protein (CREB) in a transgenic mouse model of F3/Contactin overexpression. We also investigated whether F3/Contactin might influence neuronal apoptosis and the production of amyloid-beta peptide (Aβ), known to be one of the main pathogenetic hallmarks of Alzheimer's disease (AD). In conclusion, a further understanding of F3/Contactin role in synaptic plasticity and memory might have interesting clinical outcomes in cognitive disorders, such as aging and AD, offering innovative therapeutic opportunities.
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In addition to these functions, the Contactins appear to have also a role in degenerative and inflammatory disorders: indeed Contactin 2 is involved in neurodegenerative disorders with a special reference to the Alzheimer disease, given its ability to work as a ligand of the Alzheimer Precursor Protein (APP), which results in increased Alzheimer Intracellular Domain (AICD) release in a γ-secretase-dependent manner. On the other hand Contactin 1 drives Notch signalling activation via the Hes pathway, which could be consistent with its ability to modulate neuroinflammation events, and with the possibility that Contactin 1-dependent interactions may participate to the pathogenesis of the Multiple Sclerosis and of other inflammatory disorders.
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F3 expression undergoes a progressive upregulation in different regions of the developing nervous tissue as cerebral and cerebellar cortex, hippocampus, and olfactory bulb (Bizzoca et al., 2003, 2012; Hosoya et al., 1995; Virgintino et al., 1999). These changes span early postnatal development (Gennarini et al., 1989, 1991; Virgintino et al., 1999) and persist in 5- to 12-month-old mice (Puzzo et al., 2013). Consistent with previous studies (Shimazaki et al., 1998), we found here a significant decrease of F3 expression in aged wild-type mice, thus confirming a possible correlation with age-related memory impairment.
We have recently shown that overexpression of the F3/contactin adhesive glycoprotein (also known as Contactin-1) promotes neurogenesis in adult hippocampus, which correlates with improved synaptic plasticity and memory. Because F3/contactin levels physiologically decrease with age, here, we aim at investigating whether its overexpression might counteract the cognitive decline in aged animals. For this we use 20- to 24-month-old TAG/F3 transgenic mice in which F3/contactin overexpression is driven by regulatory sequences from the gene encoding the transient axonal glycoprotein TAG-1 throughout development. We show that aged TAG/F3 mice display improved hippocampal long-term potentiation and memory compared with wild-type littermates. The same mice undergo a decrease of neuronal apoptosis at the hippocampal level, which correlated to a decrease of active caspase-3; by contrast, procaspase-3 and Bax as well as the anti-apoptotic and plasticity-related pathway BDNF/CREB/Bcl-2 were rather increased. Interestingly, amyloid-precursor protein processing was shifted toward sAPPα generation, with a decrease of sAPPβ and amyloid-beta levels. Our data confirm that F3/contactin plays a role in hippocampal synaptic plasticity and memory also in aged mice, suggesting that it acts on molecular pathways related to apoptosis and amyloid-beta production.
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F3/Contactin is a neuronal surface glycoprotein, which plays a general role in neural development and, in particular, in neuronal and oligodendrocyte differentiation. In a previous study using the F3/EGFP transgenic mice, which express an EGFP reporter under control of the regulatory region from the mouse F3/Contactin gene, the activation of the F3/Contactin promoter was found to correlate with granule and Purkinje neuron differentiation in developing cerebellar cortex. Here we report that in developing cerebral cortex and basal ganglia the F3/Contactin gene is mostly activated during early commitment of neuronal precursors, thus indicating a region-specific profile of its developmental activation. We also report that, in the same structures of F3/EGFP mice, a downregulation of the endogenous F3/Contactin gene occurs, which correlates with upregulation of the dopaminergic phenotype and with locomotor pattern abnormalities. Therefore, F3/EGFP transgenic mice exhibit morphological and functional phenotypes recapitulating those arising from imbalance of the striatal dopaminergic pathway. As for the underlying mechanisms, we postulate that in F3/EGFP mice F3/Contactin downregulation results from the ability of transgene promoter sequences to interfere with the activation of the endogenous gene, thus realizing an F3/Contactin knockdown model, while dopaminergic upregulation is consistent with a general F3/Contactin inhibitory effect on the neuronal phenotype.

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Neuron

ArticleTransfected F3/F11 neuronal cell surface protein mediates intercellular adhesion and promotes neurite outgrowth

Abstract

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Isolation and nucleotide sequence of mouse NCAM cDNA that codes for a Mr 79,000 polypeptide without a membrane-spanning region

EMBO J.

Immunohistological localization of the adhesion molecules L1, NCAM and MAG in developing and adult optic nerve of mice

J. Comp. Neurol.

Elements de Calcul des Probabilites

Distinct calcium-independent and calcium-dependent adhesion systems of chicken embryo cells

Extension of neurites on axons is impaired by antibodies against specific neural cell surface glycoproteins

J. Cell Biol.

Neural cell adhesion molecule: structure, immunoglobulin-like domains, cell surface modulation and alternative RNA splicing

Science

Article
Transfected F3/F11 neuronal cell surface protein mediates intercellular adhesion and promotes neurite outgrowth