A current view on contactin-4, -5, and -6: Implications in neurodevelopmental disorders

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Highlights

  • Contactin-4, -5, and -6 have been implicated in neurodevelopmental disorders by genetic studies.

  • Null mutation of contactin-4, -5 and -6 cause developmental abnormalities in specific and distinct brain systems.

  • The mode of action of contactin-4, -5 and -6 involves the formation of functional heterodimeric complexes.

Abstract

Contactins (Cntns) are a six-member subgroup of the immunoglobulin cell adhesion molecule superfamily (IgCAMs) with pronounced brain expression and function. Recent genetic studies of neuropsychiatric disorders have pinpointed contactin-4 (CNTN4), contactin-5 (CNTN5) and contactin-6 (CNTN6) as candidate genes in neurodevelopmental disorders, particularly in autism spectrum disorders (ASDs), but also in intellectual disability, schizophrenia (SCZ), attention-deficit hyperactivity disorder (ADHD), bipolar disorder (BD), alcohol use disorder (AUD) and anorexia nervosa (AN). This suggests that they have important functions during neurodevelopment. This suggestion is supported by data showing that neurite outgrowth, cell survival and neural circuit formation can be affected by disruption of these genes. Here, we review the current genetic data about their involvement in neuropsychiatric disorders and explore studies on how null mutations affect mouse behavior. Finally, we highlight to role of protein–protein interactions in the potential mechanism of action of Cntn4, -5 and -6 and emphasize that complexes with other membrane proteins may play a role in neuronal developmental functions.

Introduction

The development of the central nervous system is dependent on the highly coordinated interplay of diverse cells in transition. Neural cell adhesion molecules (CAMs) are indispensable for allowing such neural cell interactions and provide support in multiple neurodevelopmental processes, including cell survival, neurite outgrowth, neuronal migration, axon guidance, and synaptogenesis (Geschwind and Levitt, 2007, Pardo and Eberhart, 2007, Rubenstein, 2011). Recent neurobiological characterization of CAMs has revealed that complex physical interactions between different types of CAMs are involved in these cellular processes.

Contactins (Cntns) are proteins belonging to a specific subclass of the immunoglobulin CAM superfamily (IgCAM). They play critical roles in neuronal and glial networks. The Cntn family includes six members (Cntn1 to -6) that each exerts specific functions. (See contribution by Furley, A and Gennarini, G to this volume). Although the domain organization of Cntn members is reminiscent to that of other IgCAMs (Maness and Schachner, 2007), the structural signature of all six Cntn members consists of six N-terminal Ig domains, four fibronectin type III (FNIII) domains, and they are tethered to the cell membrane with a C-terminal glycosylphosphatidylinositol (GPI)-anchor.

Contactin-1 (Cntn1, aka F3/contactin) and contactin-2 (Cntn2, aka TAG-1) are the prototypical members of the family. They have important functions in neuron-glia interactions and formation of the nodes of Ranvier (Ascano et al., 2012, Peles and Salzer, 2000). In addition, these two proteins regulate neuronal migration, axon guidance and the organization of myelin subdomains through cis- and trans-interactions with distinct CAMs (Mohebiany et al., 2014). Cntn1 and Cntn2 may exemplify principal functions and mechanisms of action of the other members of this family However, the roles of contactin-3 (Cntn3 aka BIG-1), contactin-4 (Cntn4, aka BIG-2), contactin-5 (Cntn5, aka NB-2), and contactin-6 (Cntn6, aka NB-3) have been less well characterized. Interestingly, they have been put in the spotlights by recent genetic studies of neuropsychiatric developmental disorders including autism spectrum disorders (ASDs), identifying these members as candidate risk genes (Guo et al., 2012, Nava et al., 2014, van Daalen et al., 2011). Moreover, multiple studies using null mutant mice have indicated functions of these Cntns in the developing and mature brain (Shimoda and Watanabe, 2009).

In this review, we provide an overview on the roles of Cntn4, -5 and -6 in development of neurodevelopmental disorders, the phenotypes of null mutation in mouse models and address potential molecular mechanisms by which biological functions of are brought about.

Section snippets

Contactin-4, -5, and -6: structural and functional relationships

The six individual members of the Cntn family share an overall 40–60% amino acid identity, but comparison of individual domains between CNTN4 and CNTN3, CNTN5 and CNTN6 demonstrated an amino acid sequence identity of roughly 70% or more for the second and third Ig domains (Zuko et al., 2011). These two Ig domains are partly responsible for the horse shoe-shaped conformation of the Cntns at the N-terminus that also interacts with a common binding partner, namely the receptor protein tyrosine

Genetic implication of contactin-4, -5 and -6 in neurodevelopmental disorders

Developmental neuropsychiatric disorders are a highly heterogeneous group of diseases characterized by multi-complex genetics, variable behavioral symptoms and variable pathological distributions (Zhao and Castellanos, 2016). Copy number variations (CNVs) are structural genomic variations, either deletions or duplications, causing changes in gene dosage. Current genetic studies have shown the association of neuropsychiatric developmental disorders with CNVs in several CNTN genes (Kirov, 2015,

Behavioral phenotypes of Cntn4, -5 and -6 null mutants

In view of the face validity of the behavioral symptoms of neuropsychiatric disorders and to understand the functional consequences of mutation of neuropsychiatric candidate genes, it is necessary to employ behavioral tasks in animal models. A conceptual issue on mouse models mimicking human genetic abnormalities concerns the mouse genotypes created for analysis. Since human neuropsychiatric disorders and these can transpire differently in animals, especially, in humans the genetic defects can

Molecular mechanisms of action of contactin-4, -5 and -6

Cellular functions of Cntn4, -5, and -6 related to neurodevelopment have emerged from studies in mice deficient for these Cntn genes. Although the gross neuroanatomy was not affected (Kaneko-Goto et al., 2008, Li et al., 2003, Takeda et al., 2003), more detailed analyses in specific processes in neurodevelopment did demonstrate impairments in several neurobiological processes, including axonal guidance and outgrowth, the orientation of elongating dendrites, and synaptogenesis (Huang et al., 2012

Conclusion

Contactins 3–6 have long been the obscure members of the Cntn family. Due to genetic and neurobiological studies the latter three received more light recently. We can now conclude that Cntn4, -5 and -6 regulate developmental processes which, when affected by loss-of-function of either of these CNTNs in man, can lead to neuropsychiatric developmental disorders. The clinical phenotypes appear to be very divers, ranging from mental retardation to ASD and anorexia nervosa. This may indicate that

Acknowledgements

Authors of this review were supported by EU-AIMS (European Autism Interventions), which receives support from the Innovative Medicines Initiative Joint Undertaking under Grant agreement no.115300, there sources of which are composed of financial contributions from the European Union's Seventh Framework Programed Grant (P7/2007–2013), from the European Federation of Pharmaceutical Industries and Associations Companies' in-kind contributions, and from Autism Speaks. (K.T.E.K. and J.P.H.B.), by a

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