Abstract
In view of important neurobiological functions of the cell adhesion molecule contactin-6 (Cntn6) that have emerged from studies on null-mutant mice and autism spectrum disorders patients, we set out to examine pathways underlying functions of Cntn6 using a proteomics approach. We identified the cell adhesion GPCR latrophilin-1 (Lphn1, a.k.a. CIRL1/CL, ADGRL1) as a binding partner for Cntn6 forming together a heteromeric cis-complex. Lphn1 expression in cultured neurons caused reduction in neurite outgrowth and increase in apoptosis, which was rescued by coexpression of Cntn6. In cultured neurons derived from Cntn6-/- mice, Lphn1 knockdown reduced apoptosis, suggesting that the observed apoptosis was Lphn1-dependent. In line with these data, the number of apoptotic cells was increased in the cortex of Cntn6-/- mice compared to wild-type littermate controls. These results show that Cntn6 can modulate the activity of Lphn1 by direct binding and suggests that Cntn6 may prevent apoptosis thereby impinging on neurodevelopment.
Highlights
The six members of the contactin family of immunoglobulin cell adhesion molecules (IgCAMs) play diverse roles in the nervous system (Shimoda and Watanabe, 2009; Stoeckli, 2010; Zuko et al, 2013)
Since CNTN6 has been implicated in neurodevelopmental disorders we set out to examine pathways of action of this contactin member
We show that null-mutation of Cntn6 increases apoptosis in vitro and in vivo and that this effect involves a pathway that is dependent on the presence of the adhesion GPCR Lphn1
Summary
The six members of the contactin family of immunoglobulin cell adhesion molecules (IgCAMs) play diverse roles in the nervous system (Shimoda and Watanabe, 2009; Stoeckli, 2010; Zuko et al, 2013). Contactin-1 (Cntn, a.k.a. F3) and contactin-2 (Cntn a.k.a. Tag-1) have been well characterized for their specialized functions in neuron–glia interaction, in the paranode and juxtapararanode of the nodes of Ranvier (Peles and Salzer, 2000; Scherer and Arroyo, 2002; Poliak and Peles, 2003). The contactins act through homophilic and heterophilic interactions with various classes of proteins and form codes for specified connectivity (Stoeckli, 2010). All contactin members, except Cntn (a.k.a. NB-3) have been proposed to participate in an IgCAM code to guide lamina-specific neurite targeting (Yamagata and Sanes, 2012).
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