On the Neurobiological Role of the Autism-related Protein Contactin-6

A Zuko

Research output: ThesisDoctoral thesis 1 (Research UU / Graduation UU)


Disruption in the genes coding for the neural cell adhesion molecules contactin-4 (Cntn4), contactin-5 (Cntn5), and contactin-6 (Cntn6) contribute to an increased risk of neuropsychiatric disorders, particularly autism spectrum disorders (ASD). This indicates that the absence or dysfunction of these proteins may disrupt normal brain development. While Cntn4, Cntn5, and Cntn6 are expressed in distinct but overlapping brain regions in rodents, the gross neuroanatomy of the respective null-mutant mice is not affected. More detailed analyses of specific processes in neurodevelopment did demonstrate impairments in several neurobiological processes, including neurite outgrowth, synaptogenesis, neural survival, guiding projections and terminal branches of axons in forming neural circuits. Although studies so far indicate distinct neuroanatomical expression patterns and behavioral phenotypes in the respective null-mutant mice, very little is still known about the molecular mechanisms underlying the biological pathways in which these Cntns participate. The common structural architecture of the Cntn subgroup indicates the necessity of binding partners in order for them to facilitate any neurobiological functions. While Cntns are membrane-linked, but not membrane-spanning, the involved mechanisms of action must rely on a signalling function of the Cntn protein itself or the interaction with other membrane-spanning proteins. Abundant evidence for contactin-1 (Cntn1) and contactin-2 (Cntn2) show that cis- and trans-interaction with several membrane-spanning proteins is part of their repertoire. Therefore, the aim of this thesis is to unravel the neurobiological mechanisms of Cntn4, Cntn5, and Cntn6, with emphasis on Cntn6. Through proteomics novel and known interacting proteins were identified for these three contactins. The interaction of Cntn6 with the cell adhesion G protein-coupled receptor latrophilin-1 (Lphn1, aka CIRL, ADGRL1) was investigated in detail, showing that Cntn6 inhibited Lphn1-mediated apoptosis. These results suggest that Lphn1 functions as a dependence receptor, which induces neuronal apoptosis only in absence of Cntn6. Indeed, neuroanatomical analysis of the visual cortex of Cntn6 null-mutantmice displayed an increase in apoptosis, demonstrating the significant consequences in vivo. Furthermore, it provides a novel look into modes of action of Cntns and into the consequences for brain development. The identification of cell adhesion properties of Cntn6 in the cerebral cortex points to a broader function for Cntn6 in neurodevelopment than was previously shown. This was further emphasized by the ability of Cntn6 to interact with multiple membrane-spanning proteins with each having several interactions of their own, including the well-known and ASD-implicated Nrxn1-Nlgn1 pathway. This may represent the leading edge for integrated protein networks important for brain development, maturation and plasticity. It may provide valuable starting points for future studies to unravel how absence of Cntns impair neurobiological processes, and ultimately lead to ASD pathophysiology.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • University Medical Center (UMC) Utrecht
  • Burbach, Peter, Primary supervisor
  • Pasterkamp, Jeroen, Supervisor
  • van der Zwaag, Bert, Co-supervisor
Award date6 Oct 2015
Print ISBNs978-90-393-6402-4
Publication statusPublished - 6 Oct 2015


  • Neurodevelopment
  • ASD
  • Autism
  • Proteomics
  • Contactin
  • Cntn
  • CAM
  • Dependence
  • Receptor aGPCR


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