CNTN4 modulates neural elongation through interplay with APP
Rosemary A. Bamford,
Amila Zuko,
Madeline Eve,
Jan J. Sprengers,
Harm Post,
Renske L. R. E. Taggenbrock,
Dominique Fäβler,
Annika Mehr,
Owen J. R. Jones,
Aurimas Kudzinskas,
Josan Gandawijaya,
Ulrike C. Müller,
Martien J. H. Kas,
J. Peter H. Burbach,
Asami Oguro-Ando
Affiliations
Rosemary A. Bamford
University of Exeter Medical School, University of Exeter , Exeter EX2 5DW, UK
Amila Zuko
Department of Molecular Neurobiology, Donders Institute for Brain, Cognition and Behaviour and Faculty of Science, Radboud University , Nijmegen, The Netherlands
Madeline Eve
University of Exeter Medical School, University of Exeter , Exeter EX2 5DW, UK
Jan J. Sprengers
Department of Translational Neuroscience, UMC Utrecht Brain Center, UMC Utrecht , Utrecht 3508 AB, The Netherlands
Harm Post
Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht, Institute for Pharmaceutical Sciences, Utrecht University , Utrecht, The Netherlands
Renske L. R. E. Taggenbrock
Department of Translational Neuroscience, UMC Utrecht Brain Center, UMC Utrecht , Utrecht 3508 AB, The Netherlands
Dominique Fäβler
Institute for Pharmacy and Molecular Biotechnology (IPMB), Functional Genomics, University of Heidelberg , Heidelberg 69120, Germany
Annika Mehr
Institute for Pharmacy and Molecular Biotechnology (IPMB), Functional Genomics, University of Heidelberg , Heidelberg 69120, Germany
Owen J. R. Jones
University of Exeter Medical School, University of Exeter , Exeter EX2 5DW, UK
Aurimas Kudzinskas
University of Exeter Medical School, University of Exeter , Exeter EX2 5DW, UK
Josan Gandawijaya
University of Exeter Medical School, University of Exeter , Exeter EX2 5DW, UK
Ulrike C. Müller
Institute for Pharmacy and Molecular Biotechnology (IPMB), Functional Genomics, University of Heidelberg , Heidelberg 69120, Germany
Martien J. H. Kas
Department of Translational Neuroscience, UMC Utrecht Brain Center, UMC Utrecht , Utrecht 3508 AB, The Netherlands
J. Peter H. Burbach
Department of Translational Neuroscience, UMC Utrecht Brain Center, UMC Utrecht , Utrecht 3508 AB, The Netherlands
Asami Oguro-Ando
University of Exeter Medical School, University of Exeter , Exeter EX2 5DW, UK
The neuronal cell adhesion molecule contactin-4 (CNTN4) is genetically associated with autism spectrum disorder (ASD) and other psychiatric disorders. Cntn4-deficient mouse models have previously shown that CNTN4 plays important roles in axon guidance and synaptic plasticity in the hippocampus. However, the pathogenesis and functional role of CNTN4 in the cortex has not yet been investigated. Our study found a reduction in cortical thickness in the motor cortex of Cntn4 −/− mice, but cortical cell migration and differentiation were unaffected. Significant morphological changes were observed in neurons in the M1 region of the motor cortex, indicating that CNTN4 is also involved in the morphology and spine density of neurons in the motor cortex. Furthermore, mass spectrometry analysis identified an interaction partner for CNTN4, confirming an interaction between CNTN4 and amyloid-precursor protein (APP). Knockout human cells for CNTN4 and/or APP revealed a relationship between CNTN4 and APP. This study demonstrates that CNTN4 contributes to cortical development and that binding and interplay with APP controls neural elongation. This is an important finding for understanding the physiological function of APP, a key protein for Alzheimer’s disease. The binding between CNTN4 and APP, which is involved in neurodevelopment, is essential for healthy nerve outgrowth.
