Yiliang Xu1,2 · Tian Zhao1,2 · Dan Zhao1,2 · Wei Zhang1  · Di Mu1  · Ailing Gui1  · Junzhi Guo1,2 · Kazutada Watanabe3  · Zhi‑Cheng Xiao4,5 · Haihong Ye1,2

1 Department of Medical Genetics and Developmental Biology, School of Basic Medical Science, Capital Medical University, Beijing 100069, China 

2 Laboratory for Clinical Medicine, Capital Medical University, Beijing 100069, China 

3 Department of Bioengineering, Nagaoka University of Technology, Nagaoka 940‑2188, Japan 

4 Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia 

5 Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing 312099, China

Abstract

Contactin-6 (CNTN6) is a membrane protein that belongs to the contactin subgroup of the immunoglobulin (Ig) superfamily. Substantial evidence supports a significant role of its encoding gene, CNTN6, in neurodevelopment and psychiatric disorders, including autism spectrum disorders and schizophrenia. Further studies are required to clarify the role of CNTN6 in the etiology of these disorders. Here, we show that the first three Ig domains of the extracellular region of CNTN6 compete with Robo2 for binding to the leucine-rich repeat (LRR) domain of Slit2 and inhibit Slit-Robo signaling, thereby regulating neurite outgrowth in cortical neurons. The repulsive effect of Slit2 on the migration of GABAergic neurons was attenuated by the interaction between CNTN6 and Slit2, both in vitro and ex vivo. Male mice deficient in Cntn6 exhibited a significant reduction in the number of calbindin-positive GABAergic neurons in the motor cortex. Cntn6-null male mice also exhibited impaired social recognition and disrupted self-grooming behavior. These findings suggest that CNTN6 inhibits Slit-Robo signaling and modulates the migration of a subset of GABAergic neurons, thereby contributing to the development of autism-related behaviors associated with CNTN6 dysfunction.

Keywords

CNTN6; Slit2; GABAergic interneuron; Migration; Autism spectrum disorder

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