TAG-1-Deficient Mice Have Marked Elevation of Adenosine A1 Receptors in the Hippocampus

doi:10.1006/bbrc.2001.4334

Biochemical and Biophysical Research Communications

Volume 281, Issue 1, 16 February 2001, Pages 220-226

https://doi.org/10.1006/bbrc.2001.4334 Get rights and content

Abstract

TAG-1 is a neural recognition molecule in the immunoglobulin superfamily that is predominantly expressed in the developing brain. Several lines of evidence suggest that TAG-1 is involved in the outgrowth, guidance, and fasciculation of neurites. To directly assess the function of TAG-1 in vivo, we have generated mice with a deletion in the gene encoding TAG-1 using homologous recombination in embryonic stem cells. Gross morphological analysis of the cerebellum, the spinal cord, and the hippocampus appeared normal in TAG-1-deficient mice. However, TAG-1 (−/−) mice showed the upregulation of the adenosine A1 receptors determined by [³H]cyclopentyl-1,3-dipropylxanthine in the hippocampus, and their greater sensitivity to convulsant stimuli than that in TAG-1 (+/+) mice. We suspect that the subtle changes in neural plasticity induced by TAG-1 deficiency during development cause the selective vulnerability of specific brain regions and the epileptogenicity in TAG-1 (−/−) mice.

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Neonatal encephalopathy (NE) impairs white matter development and results in long-term neurodevelopmental deficits. Leveraging prior findings of altered neuronal proteins carried by brain-derived extracellular vesicles (EVs) that are marked by a neural-specific cell surface glycoprotein Contactin-2 (CNTN2) in NE infants, the present study aimed to determine the correlation between brain and circulating CNTN2⁺-EVs and whether NE alters circulating CNTN2⁺-EV levels in mice. Brain tissue and plasma were collected from postnatal day (P)7, 10, 11, 15 mice to determine the baseline CNTN2 correlation between these two compartments (n = 4–7/time point/sex). NE was induced in P10 pups. Brain and plasma samples were collected at 1, 3, 6, 24, and 120 h (n = 4–8/time point/sex). CNTN2 from brain tissue and plasma EVs were quantified using ELISA. ANOVA and linear regression analyses were used to evaluate changes and correlations between brain and plasma CNTN2⁺-EVs. In baseline experiments, CNTN2 in brain tissue and plasma EVs peaked at P10 with no sex-difference. Brain and plasma CNTN2⁺-EV showed a positive correlation across early postnatal ages. NE pups showed an elevated CNTN2 in brain tissue and EVs at 1 h and only in brain tissue at 24 h. NE also abolished the positive plasma-brain correlation. The findings establish a link for central CNTN2 and its release into circulation during early postnatal life. The immediate elevation and release of CNTN2 following NE highlight a potential molecular response shortly after a brain injurious event. Our findings further support the utility of circulating brain-derived EVs as a possible bioindicator of NE.
TAG-1 Multifunctionality Coordinates Neuronal Migration, Axon Guidance, and Fasciculation
2020, Cell Reports
Neuronal migration, axon fasciculation, and axon guidance need to be closely coordinated for neural circuit assembly. Spinal motor neurons (MNs) face unique challenges during development because their cell bodies reside within the central nervous system (CNS) and their axons project to various targets in the body periphery. The molecular mechanisms that contain MN somata within the spinal cord while allowing their axons to exit the CNS and navigate to their final destinations remain incompletely understood. We find that the MN cell surface protein TAG-1 anchors MN cell bodies in the spinal cord to prevent their emigration, mediates motor axon fasciculation during CNS exit, and guides motor axons past dorsal root ganglia. TAG-1 executes these varied functions in MN development independently of one another. Our results identify TAG-1 as a key multifunctional regulator of MN wiring that coordinates neuronal migration, axon fasciculation, and axon guidance.
The role of Gpi-anchored axonal glycoproteins in neural development and neurological disorders
2017, Molecular and Cellular Neuroscience
Citation Excerpt :
Knockout of Cntn2 (Cntn2ko) in mice has not revealed evidence of a critical role in some of the key systems in which it has been implicated from the above-described expression profile. Two independent Cntn2ko mutants are each homozygous viable and display no gross phenotypes in the brain or spinal cord (Fukamauchi et al., 2001; Poliak et al., 2003), although a predisposition to seizures (Fukamauchi et al., 2001) and failure to gain weight in response to high fat diet (Buchner et al., 2012) have been reported. Extensive axon tracing analysis of commissural axon trajectories revealed no evidence (Yeomans, Kiernan and Furley, unpublished) of the dramatic pathfinding defects found using a variety of acute function blocking methodologies in chick (Stoeckli and Landmesser, 1995), where CNTN2 has been implicated in interactions with midline-expressed NrCAM in the switching of C axon sensitivities to floor plate-derived repellants (Stoeckli et al., 1997; Pekarik et al., 2003), one of which has been identified to be Semaphorin3B (Nawabi et al., 2010).
This review article focuses on the Contactin (CNTN) subset of the Immunoglobulin supergene family (IgC2/FNIII molecules), whose components share structural properties (the association of Immunoglobulin type C2 with Fibronectin type III domains), as well as a general role in cell contact formation and axonal growth control. IgC2/FNIII molecules include 6 highly related components (CNTN 1–6), associated with the cell membrane via a Glycosyl Phosphatidyl Inositol (GPI)-containing lipid tail. Contactin 1 and Contactin 2 share ~ 50 (49.38)% identity at the aminoacid level. They are components of the cell surface, from which they may be released in soluble forms. They bind heterophilically to multiple partners in cis and in trans, including members of the related L1CAM family and of the Neurexin family Contactin-associated proteins (CNTNAPs or Casprs). Such interactions are important for organising the neuronal membrane, as well as for modulating the growth and pathfinding of axon tracts. In addition, they also mediate the functional maturation of axons by promoting their interactions with myelinating cells at the nodal, paranodal and juxtaparanodal regions. Such interactions also mediate differential ionic channels (both Na⁺ and K⁺) distribution, which is of critical relevance in the generation of the peak-shaped action potential. Indeed, thanks to their interactions with Ankyrin G, Na⁺ channels map within the nodal regions, where they drive axonal depolarization. However, no ionic channels are found in the flanking Contactin1-containing paranodal regions, where CNTN1 interactions with Caspr1 and with the Ig superfamily component Neurofascin 155 in cis and in trans, respectively, build a molecular barrier between the node and the juxtaparanode. In this region K⁺ channels are clustered, depending upon molecular interactions with Contactin 2 and with Caspr2.
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.
SynCAMs – From axon guidance to neurodevelopmental disorders
2017, Molecular and Cellular Neuroscience
Citation Excerpt :
However, in specific contexts or in combination, deletion of IgSF CAMs clearly interfered with axon guidance. For instance, mice lacking Contactin2 (Fukamauchi et al., 2001) did not display midline crossing defects in the spinal cord, despite the fact that acute perturbation of Contactin2 function by injection of function-blocking antibodies (Stoeckli and Landmesser, 1995) or knockdown of Contactin2 by in ovo RNAi (Pekarik et al., 2003) did interfere with axon guidance. However, the analysis of sensory neural circuit formation in knockout mice lacking Contactin2 (Law et al., 2008) did reveal similar phenotypes as those observed after acute loss of Contactin2 function in chicken embryos (Perrin et al., 2001) and in zebrafish (Liu and Halloran, 2005).
Many cell adhesion molecules are located at synapses but only few of them can be considered synaptic cell adhesion molecules in the strict sense. Besides the Neurexins and Neuroligins, the LRRTMs (leucine rich repeat transmembrane proteins) and the SynCAMs/CADMs can induce synapse formation when expressed in non-neuronal cells and therefore are true synaptic cell adhesion molecules. SynCAMs (synaptic cell adhesion molecules) are a subfamily of the immunoglobulin superfamily of cell adhesion molecules. As suggested by their name, they were first identified as cell adhesion molecules at the synapse which were sufficient to trigger synapse formation. They also contribute to myelination by mediating axon-glia cell contacts. More recently, their role in earlier stages of neural circuit formation was demonstrated, as they also guide axons both in the peripheral and in the central nervous system. Mutations in SynCAM genes were found in patients diagnosed with autism spectrum disorders. The diverse functions of SynCAMs during development suggest that neurodevelopmental disorders are not only due to defects in synaptic plasticity. Rather, early steps of neural circuit formation are likely to contribute.
Rational search for genes in familial cortical myoclonic tremor with epilepsy, clues from recent advances
2016, Seizure
Citation Excerpt :
Combining linkage analysis and WES, they identified a rare frameshift mutation c.503delG (p.Trp168CysfsX163) of the CNTN2 (i.e., contactin 2, 1q32.1) gene, which co-segregated in the pedigree [25]. CNTN2-deficient mice showed spontaneous epileptic seizures and increased seizure susceptibility to convulsive stimuli [27]. This observation highly supported the role of the CNTN2 gene as the underlying causative gene in this pedigree and phenotype.
Familial cortical myoclonic tremor with epilepsy (FCMTE) is an autosomal dominant epilepsy syndrome with considerable clinical and genetic heterogeneity. The most important clinical manifestations include adult onset, cortical myoclonic tremor, with or without epileptic seizures. Of the four loci reported, which included 8q24 (FCMTE1), 2p11.1-q12.2 (FCMTE2), 5p15.31-p15.1 (FCMTE3), and 3q26.32-3q28 (FCMTE4), only one probably causative mutation was found co-segregated in two FCMTE2 pedigrees in the α₂-adrenergic receptor subtype B (ADRA2B) gene. In this review we discuss studies that focused on the molecular genetics of FCMTE, its neuropathology, clinical, neurophysiological and neuroimaging features, which may offer useful clues for the search for causative FCMTE genes. Next-generation sequencing has identified many causative genes in monogenic diseases. However, most next-generation sequencing applications focus on detecting single nucleotide variants or small insertions/deletions, which do not completely resolve the challenge of identifying causative genes in FCMTE. Recent progress in exploring FCMTE has revealed that special mutations such as copy number variants, exon rearrangements and large trinucleotide repeat expansion (or polynucleotide repeat expansion) should be considered. Clues from neuropathological, clinical, neurophysiological and neuroimaging studies indicate that the candidate causative genes should be expressed in the cerebellum, especially in Purkinje cells, and be associated with calcium signaling and GABA receptors. We propose that the developing novel algorithms of next-generation sequencing data, which could detect structure variants and candidate causative gene selection when combined with special mutations detection analysis represent possible future direction of a rational search for causative genes in FCMTE.
Pioneering axons regulate neuronal polarization in the developing cerebral cortex
2014, Neuron
Citation Excerpt :
Although the results obtained in the present study suggest that TAG-1 is a key regulator of neuronal polarization, the neuronal polarization in the TAG-1 knockout (KO) mouse is not substantially changed (Denaxa et al., 2005; Fukamauchi et al., 2001; Savvaki et al., 2008). Previous studies using functional blocking experiment with neutralizing antibodies against TAG-1 suggest that TAG-1 is also involved in the neuronal migration and axon extension (Denaxa et al., 2005; Morante-Oria et al., 2003; Wang et al., 2011); however, some of these phenotypes were not apparent in the TAG-1 KO mice (Denaxa et al., 2005; Fukamauchi et al., 2001). The differences that are often observed in the results from KO analysis, and the results from knockdown analysis might be related to the experimental time window (Denaxa et al., 2005; Wang et al., 2011): one time window that suppresses gene expression throughout development and another that silences gene expression for a portion of development.
The polarization of neurons, which mainly includes the differentiation of axons and dendrites, is regulated by cell-autonomous and non-cell-autonomous factors. In the developing central nervous system, neuronal development occurs in a heterogeneous environment that also comprises extracellular matrices, radial glial cells, and neurons. Although many cell-autonomous factors that affect neuronal polarization have been identified, the microenvironmental cues involved in neuronal polarization remain largely unknown. Here, we show that neuronal polarization occurs in a microenvironment in the lower intermediate zone, where the cell adhesion molecule transient axonal glycoprotein-1 (TAG-1) is expressed in cortical efferent axons. The immature neurites of multipolar cells closely contact TAG-1-positive axons and generate axons. Inhibition of TAG-1-mediated cell-to-cell interaction or its downstream kinase Lyn impairs neuronal polarization. These results show that the TAG-1-mediated cell-to-cell interaction between the unpolarized multipolar cells and the pioneering axons regulates the polarization of multipolar cells partly through Lyn kinase and Rac1.

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¹: To whom correspondence should be addressed. Fax: +81-3-5280-8061. E-mail: [email protected].

²: Present address: Institute for Experimental Animals, School of Medicine, Kanazawa University, Takaramachi, Kanazawa-city, Ishikawa 920-8640, Japan.

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Biochemical and Biophysical Research Communications

Abstract

References (28)

The axonal glycoprotein TAG-1 is an immunoglobulin superfamily member with neurite outgrowth-promoting activity

Cell

The human TAX-1 gene encoding the axon-associated cell adhesion molecule TAG-1/axonin-1: Genomic structure and basic promoter

Genomics

Novel neural adhesion molecules in the contactin/F3 subgroup of the immunoglobulin superfamily: Isolation and characterization of cDNAs from rat brain

Neurosci. Lett.

TAG-1 can mediate homophilic binding, but neurite outgrowth on TAG-1 requires an L1-like molecule and β1 integrins

Neuron

Cis-activation of L1-mediated ankyrin recruitment by TAG-1 homophilic cell adhesion

J. Biol. Chem.

A novel negative selection for homologous recombinants using diphtheria toxin A fragment gene

Anal. Biochem.

Involvement of gangliosides in GPI-anchored neuronal cell adhesion molecule TAG-1 signaling in lipid rafts

J. Biol. Chem.

Axonin-1, Nr-CAM, and NgCAM play different roles in the in vivo guidance of chick commissural neurons

Neuron

Ataxia and abnormal cerebellar microorganization in mice with ablated contactin gene expression

Neuron

Towards a revised nomenclature for P1 and P2 receptors

Trends. Pharmacol. Sci.

Paradoxical behavioral response to apomorphine in tenascin-gene knockout mouse

Eur. J. Pharmacol.

The gene of chicken axonin-1

Eur. J. Biochem.

The axonally secreted cell adhesion molecule axonin-1, primary structure, immunoglobulin-like and fibronectin type III-like domains and glycosyl-phosphatidylinositol anchorage

Eur. J. Biochem.

Cited by (61)

Neonatal Hypoxia-Ischemia alters Brain-Derived Contactin-2-Positive Extracellular Vesicles in the Mouse Plasma

TAG-1 Multifunctionality Coordinates Neuronal Migration, Axon Guidance, and Fasciculation

The role of Gpi-anchored axonal glycoproteins in neural development and neurological disorders

SynCAMs – From axon guidance to neurodevelopmental disorders

Rational search for genes in familial cortical myoclonic tremor with epilepsy, clues from recent advances

Pioneering axons regulate neuronal polarization in the developing cerebral cortex

Regular ArticleTAG-1-Deficient Mice Have Marked Elevation of Adenosine A1 Receptors in the Hippocampus

Abstract

Cell

Genomics

Neurosci. Lett.

Neuron

J. Biol. Chem.

Anal. Biochem.

J. Biol. Chem.

Neuron

Neuron

Trends. Pharmacol. Sci.

Eur. J. Pharmacol.

The gene of chicken axonin-1

Eur. J. Biochem.

The axonally secreted cell adhesion molecule axonin-1, primary structure, immunoglobulin-like and fibronectin type III-like domains and glycosyl-phosphatidylinositol anchorage

Eur. J. Biochem.

Regular Article
TAG-1-Deficient Mice Have Marked Elevation of Adenosine A1 Receptors in the Hippocampus