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

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.     

Contactin‐associated protein‐like 2, a protein of the neurexin family involved in several human diseases

Contactin‐associated protein‐like 2 (CASPR2) is a cell adhesion protein of the neurexin family. Proteins of this family have been shown to play a role in the development of the nervous system, in synaptic functions, and in neurological diseases. Over recent years, CASPR2 function has gained an increasing interest as demonstrated by the growing number of publications. Here, we gather published data to comprehensively review CASPR2 functions within the nervous system in relation to CASPR2‐related diseases in humans. On the one hand, studies on Cntnap2 (coding for CASPR2) knockout mice revealed its role during development, especially, in setting‐up the inhibitory network. Consistent with this result, mutations in the CNTNAP2 gene coding for CASPR2 in human have been identified in neurodevelopmental disorders such as autism, intellectual disability, and epilepsy. On the other hand, CASPR2 was shown to play a role beyond development, in the localization of voltage‐gated potassium channel (VGKC) complex that is composed of TAG‐1, Kv1.1, and Kv1.2. This complex was found in several subcellular compartments essential for action potential propagation: the node of Ranvier, the axon initial segment, and the synapse. In line with a role of CASPR2 in the mature nervous system, neurological autoimmune diseases have been described in patients without neurodevelopmental disorders but with antibodies directed against CASPR2. These autoimmune diseases were of two types: central with memory disorders and temporal lobe seizures, or peripheral with muscular hyperactivity. Overall, we review the up‐to‐date knowledge on CASPR2 function and pinpoint confused or lacking information that will need further investigation.     

Axonal transport in neurological disease

The axonal transport systems have a wide variety of primary roles and secondary responses in neurological disease processes. Recent advances in understanding these roles have built on the increasingly detailed insights into the cell biology of the axon and its supporting cells. Fast transport is a microtubule-based system of bidirectional movement of membranous organelles; the mechanism of translocation of these organelles involves novel proteins, including the recently described protein of fast anterograde transport, kinesin. Slow transport conveys the major cytoskeletal elements, microtubules, and neurofilaments. Several types of structural changes in diseased nerve fibers are understood in terms of underlying transport abnormalities. Altered slow transport of neurofilaments produces changes in axonal caliber (swelling or atrophy) and is involved in some types of perikaryal neurofibrillary abnormality. Secondary changes in slow axonal transport--for example, the reordered synthesis and delivery of cytoskeletal proteins after axotomy--also can produce changes in axonal caliber. Secondary demyelination can be a prominent late consequence of a sustained alteration of neurofilament transport. Impaired fast transport is found in experimental models of distal axonal degeneration (dying back). Retrograde axonal transport provides access to the central nervous system for agents such as polio virus and tetanus toxin, as well as access for known and hypothetical trophic factors. Correlative studies of axonal transport, axonal morphometry, cytoskeletal ultrastructure, and molecular biology of cytoskeletal proteins are providing extremely detailed reconstructions of the pathogenesis of experimental models of neurological disorders. A major challenge lies in the extension of these approaches to clinical studies.     

The axon initial segment in nervous system disease and injury

The axon initial segment (AIS), with its dense clusters of voltage-gated ion channels decorating the axonal membrane, regulates action potential initiation and modulation. The AIS also functions as a barrier to maintain axodendritic polarity, and its precise axonal location contributes to the fine-tuning of neuronal excitability. Therefore, it is not surprising that mutations in AIS-related genes, disruption of the molecular organization of the AIS and altered AIS ion channel expression, function, location and/or density are emerging as key players in neurological disorders. Here, we consider the role of the AIS in nervous system disease and injury.     

Modulation of dendritic spine development and plasticity by BDNF and vesicular trafficking: fundamental roles in neurodevelopmental disorders associated with mental retardation and autism

The process of axonal and dendritic development establishes the synaptic circuitry of the central nervous system (CNS) and is the result of interactions between intrinsic molecular factors and the external environment. One growth factor that has a compelling function in neuronal development is the neurotrophin brain-derived neurotrophic factor (BDNF). BDNF participates in axonal and dendritic differentiation during embryonic stages of neuronal development, as well as in the formation and maturation of dendritic spines during postnatal development. Recent studies have also implicated vesicular trafficking of BDNF via secretory vesicles, and both secretory and endosomal trafficking of vesicles containing synaptic proteins, such as neurotransmitter and neurotrophin receptors, in the regulation of axonal and dendritic differentiation, and in dendritic spine morphogenesis. Several genes that are either mutated or deregulated in neurodevelopmental disorders associated with mental retardation have now been identified, and several mouse models of these disorders have been generated and characterized. Interestingly, abnormalities in dendritic and synaptic structure are consistently observed in human neurodevelopmental disorders associated with mental retardation, and in mouse models of these disorders as well. Abnormalities in dendritic and synaptic differentiation are thought to underlie altered synaptic function and network connectivity, thus contributing to the clinical outcome. Here, we review the roles of BDNF and vesicular trafficking in axonal and dendritic differentiation in the context of dendritic and axonal morphological impairments commonly observed in neurodevelopmental disorders associated with mental retardation.     

Plexin-B family members demonstrate non-redundant expression patterns in the developing mouse nervous system: an anatomical basis for morphogenetic effects of Sema4D during development

Semaphorins and their receptors play important roles in patterning the connectivity of the developing nervous system and recent data suggest that members of the plexin-B family of semaphorin receptors may be involved in axonal guidance. Here we show that the mRNAs of the three plexin-B genes, plxnb1, plxnb2 and plxnb3 (plexin-B1, plexin-B2 and plexin-B3), respectively, are expressed in highly specific and non-redundant patterns in peripheral and central components of the nervous system over defined periods during murine development. Whereas plexin-B1 and plexin-B2 are strongly expressed in the neuroepithelium and developing neurons, plexin-B3 mRNA is selectively localized to the white matter. Moreover, plexin-B1 and its ligand Sema4D are expressed in complementary patterns in several regions such as the developing neopallial cortex, the dorsal root ganglia and the spinal cord over embryonic stages. The Sema4d gene demonstrates a dramatic switch from prenatal expression in neuronal populations to a postnatal expression in oligodendrocytes. In contrast to its collapsing activity on growth cones of embryonic retinal ganglion cells and hippocampal neurons, soluble Sema4D enhances axonal outgrowth in embryonic cortical explants cultured in collagen matrices. Thus, plexin-B family members and Sema4D are likely to play complex and non-redundant roles during the development of the nervous system.     

More than being protective: functional roles for TGF-β/activin signaling pathways at central synapses

It is becoming increasingly clear that members of the transforming growth factor-β (TGF-β) family have roles in the central nervous system that extend beyond their well-established roles as neurotrophic and neuroprotective factors. Recent findings have indicated that the TGF-β signaling pathways are involved in the modulation of both excitatory and inhibitory synaptic transmission in the adult mammalian brain. In this review, we discuss how TGF-β, bone morphogenetic protein and activin signaling at central synapses modulate synaptic plasticity, cognition and affective behavior. We also discuss the implications of these findings for the molecular understanding and potential treatment of neuropsychiatric diseases, such as anxiety, depression and other neurological disorders.     

The SCG10-related gene family in the developing rat retina: persistent expression of SCLIP and stathmin in mature ganglion cell layer

Neuronal growth-associated proteins (GAPs), such as GAP-43 and SCG10, are thought to play crucial roles in both axonal and dendritic outgrowth during neural development and regeneration, although the underlying mechanisms remain largely unknown. The recent finding that SCG10 is a microtubule regulator and also the identification of RB3 and SCLIP as two new SCG10-related members prompted us to investigate the roles of SCG10-related family in neural development, using the retina as a model system. We determined the temporal expression and the spatial distribution of SCG10-related mRNAs in the developing rat retina. Semiquantitative analysis by RT-PCR revealed that in prenatal retina, levels of SCG10 and stathmin mRNAs were higher than those of RB3 and SCLIP. In the postnatal retina, the level of SCLIP increased, whereas the level of RB3 remained low. In situ hybridization revealed that GAP-43 and all of the SCG10-related family mRNAs were present in the retinal ganglion cells (RGCs) at all stages of retinal development, and that stathmin mRNA was present in mitotic neuroblastic cells. Differential expression of SCG10 and other members of the family became more evident as retinal development proceeded; SCG10 and RB3 expression were relatively specific in the RGCs and amacrine cells, whereas SCLIP was also evident in bipolar and horizontal cells. Stathmin mRNA was highly expressed both in the RGCs and other interneurons. These results indicate that multiple SCG10-related proteins are expressed in single neurons including RGCs, and suggest that these nGAPs play similar but distinct roles in differentiation and functional maintenance of retinal neurons.     

Activation profile of the F3/Contactin gene in the developing mouse cerebellum

In this study, we address the activation profile of the gene encoding the mouse axonal glycoprotein F3/Contactin. Promoter sequences previously characterized in vitro are used to drive an Enhanced Green Fluorescent Protein reporter in transgenic mice. In developing cerebellum, differential transgene expression occurs within distinct cell populations. At P0 the transgene is activated in postmitotic granule neurons undergoing radial migration, a sharp upregulation occurring at P6-P8, with a gradual decline from this stage onward. In Purkinje cells, promoter activation, first detected at P3, peaks at around P6 and is fully downregulated by P16. The transgene is also expressed in Ng2- and O4-positive cells, mostly at the end of the first postnatal week, suggesting correlation with early oligodendrocyte differentiation. These data indicate that the complex organization of the regulatory region of the F3/Contactin gene is necessary for directing its articulated expression in different neural cells types and for its developmental function.     

Slitrks as emerging candidate genes involved in neuropsychiatric disorders

Slitrks are a family of structurally related transmembrane proteins belonging to the leucine-rich repeat (LRR) superfamily. Six family members exist (Slitrk1-6) and all are highly expressed in the central nervous system (CNS). Slitrks have been implicated in mediating basic neuronal processes, ranging from neurite outgrowth and dendritic elaboration to neuronal survival. Recent studies in humans and genetic mouse models have led to the identification of Slitrks as candidate genes that might be involved in the development of neuropsychiatric conditions, such as obsessive compulsive spectrum disorders and schizophrenia. Although these system-level approaches have suggested that Slitrks play prominent roles in CNS development, key questions remain regarding the molecular mechanisms through which they mediate neuronal signaling and connectivity.     

Abnormalities in FGF family members and their roles in modulating depression‐related molecules

The role of the fibroblast growth factor (FGF) system in depression has received considerable attention in recent years. To understand the role of this system, it is important to identify the specific members of the FGF family that have been implicated and the various mechanisms that they modulated. Here, we review the role of FGFs in depression and integrate evidence from clinical and basic research. These data suggest that changes in the FGF family are involved in depression and possibly in a wider range of psychiatric disorders. We analyse the abnormalities of FGF family members in depression and their roles in modulating depression‐related molecules. The role of the FGF family in depression and related disorders needs to be studied in more detail.     

The role of NrCAM in neural development and disorders--beyond a simple glue in the brain

NrCAM is a neuronal cell adhesion molecule of the L1 family of immunoglobulin super family. It plays a wide variety of roles in neural development, including cell proliferation and differentiation, axon growth and guidance, synapse formation, and the formation of the myelinated nerve structure. NrCAM functions in cell adhesion and modulates signaling pathways in neural development through multiple molecular interactions with guidance and other factors. Alterations in NrCAM structure/expression are associated with psychiatric disorders such as autism and drug addiction and with tumor progression. The mechanisms of NrCAM participation in development and how these might be perturbed in disorders are reviewed.     

Role of chemokines in ischemic neuronal stress

Chemokines constitute a large family of structurally related small cytokines originally identified as the factors regulating the migration of leukocytes in inflammatory and immune responses. Enhanced production and release of chemokines are observed also in the central nervous system under diverse neuronal stresses including ischemia, axonal injury, and neurotoxic substances such as an Abeta-peptide. There is growing evidence that brain chemokines play crucial roles in the neuro-glio-vascular interaction underlying the pathology of various brain disorders. Here the evidence of the involvement of chemokines in ischemic brain injury is reviewed.     

Neuroaxonal dystrophy in neuronal storage disorders: evidence for major GABAergic neuron involvement

The formation of focal granular enlargements within axons (axonal spheroids or "torpedoes"; neuroaxonal dystrophy) is a well known phenomenon occurring in a variety of neurological diseases. The relative susceptibility of different types of neurons to this kind of axonal pathology, however, is largely unknown. An immunocytochemical study directed at localizing glutamic acid decarboxylase (GAD), the synthetic enzyme for the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), in various CNS regions in feline models of lysosomal storage disorders has revealed vast numbers of axonal spheroids containing this enzyme. In some storage diseases (GM1 and GM2 gangliosidosis), GAD-immunoreactive spheroids were a common occurrence in many brain regions, whereas in other disorders these structures were more limited in distribution (alpha-mannosidosis), or were absent (mucopolysaccharidosis type I). Axonal spheroids unreactive for GAD were encountered in large numbers in subcortical white matter in GM2 gangliosidosis, but were infrequently observed in the other diseases. The incidence and distribution of GAD-immunoreactive spheroids in the various diseases under study were found to correlate closely with the type and degree of neurological deficits exhibited by affected animals. This study indicates that the neuroaxonal dystrophy occurring in some types of storage disorders commonly involves axons of GABAergic neurons and suggests that a resulting defect in neurotransmission in inhibitory circuits may be an important factor underlying brain dysfunction in this family of diseases.     

Involvement of leak K~+ channels in neurological disorders

TWIK-related acid-sensitive K+(TASK) channels give rise to leak K+ currents which influence the resting membrane potential and input resistance. The wide expression of TASK1 and TASK3 channels in the central nervous system suggests that these channels are critically involved in neurological disorders. It has become apparent in the past decade that TASK channels play critical roles for the development of various neurological disorders. In this review, I describe evidence for their roles in ischemia, epilepsy, learning/memory/cognition and apoptosis.     

Neuregulins: versatile growth and differentiation factors in nervous system development and human disease

The neuregulins are a family of growth and differentiation factors with a wide range of functions in the nervous system. The power and diversity of the neuregulin signaling system comes in part from a large number of alternatively-spliced forms of the NRG1 gene that can produce both soluble and membrane-bound forms. The soluble forms of neuregulin are unique from other factors in that they have a structurally distinct heparin-binding domain that targets and potentiates its actions. In addition, a finely tuned, bidirectional mechanism regulates when and where neuregulin is released from neurons in response to neurotrophic factors produced by both neuronal targets and supporting glial cells. Together, this produces a balanced intercellular signaling system that can be localized to distinct regions for both normal development and maintenance of the mature nervous system. Recent evidence suggests that neuregulin signaling plays important roles in many neurological disorders including multiple sclerosis, traumatic brain and spinal cord injury, peripheral neuropathy, and schizophrenia. Here, we review the basic biology of neuregulins and relate this to research suggesting their involvement with and potential therapeutic uses for neurological disorders.     

Axon pruning and synaptic development: how are they per-plexin?

During the development of the nervous system, neurons must first migrate to their appropriate locations and then send out axons to make connections. Various environmental cues guide these migrating neurons and growing axons. After axons reach their target regions, neuronal contacts are created through the formation of synapses. Because excess axonal branches and synaptic contacts are often formed during early development, they are pruned or eliminated at later stages to create specific neuronal connections. Several groups of ligand-receptor pairs have been identified to regulate each of these cellular events. Evidence also indicates that these same molecules may be used in multiple developmental processes. Here, we discuss semaphorins and plexins, the largest family of axon guidance ligand-receptor pairs. Because the roles of semaphorins in neuronal migration and axonal repulsion have been extensively reviewed, we will focus on plexin receptors. We will discuss how semaphorin signals are specifically passed through these receptors into cells and how plexins mediate their newly identified roles in axon pruning and synaptic development.