γ-Protocadherins Interact with Neuroligin-1 and Negatively Regulate Dendritic Spine Morphogenesis

Publication date: 14 March 2017
Source:Cell Reports, Volume 18, Issue 11
Author(s): Michael J. Molumby, Rachel M. Anderson, Dillan J. Newbold, Norah K. Koblesky, Andrew M. Garrett, Dietmar Schreiner, Jason J. Radley, Joshua A. Weiner
The 22 γ-Protocadherin (γ-Pcdh) cell adhesion molecules are critical for the elaboration of complex dendritic arbors in the cerebral cortex. Here, we provide evidence that the γ-Pcdhs negatively regulate synapse development by inhibiting the postsynaptic cell adhesion molecule, neuroligin-1 (Nlg1). Mice lacking all γ-Pcdhs in the forebrain exhibit significantly increased dendritic spine density in vivo, while spine density is significantly decreased in mice overexpressing one of the 22 γ-Pcdh isoforms. Co-expression of γ-Pcdhs inhibits the ability of Nlg1 to increase spine density and to induce presynaptic differentiation in hippocampal neurons in vitro. The γ-Pcdhs physically interact in cis with Nlg1 both in vitro and in vivo, and we present evidence that this disrupts Nlg1 binding to its presynaptic partner neurexin1β. Together with prior work, these data identify a mechanism through which γ-Pcdhs could coordinate dendrite arbor growth and complexity with spine maturation in the developing brain.

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Teaser

Using conditional mutant and overexpression mouse lines, Molumby et al. demonstrate that γ-Protocadherins negatively regulate cortical dendritic spine morphogenesis in vivo. The γ-Protocadherins interact physically with neuroligin-1 and inhibit its ability to bind neurexin1β, to promote presynaptic differentiation, and to increase dendritic spine density in hippocampal neurons in vitro.


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