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

Abstract

SUMMARY 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.

Regulation of neural circuit formation by protocadherins

“…Consistent with this, overexpression of a single γ-Pcdh isoform (γ-Pcdh-A1) in the cortex in vivo using a Cre-activated transgenic mouse line resulted in significantly decreased overall spine density, due to reductions in mushroom and thin spines accompanied by a smaller increase in stubby spines [108]. Furthermore, co-expression of a γ-Pcdh isoform can inhibit the increase in spine density seen in cultured hippocampal neurons following overexpression of neuroligin-1 [108]. Thus, in the cortex in vivo the γ-Pcdhs may actually inhibit spine formation and/or stabilization, perhaps in favor of promoting dendrite arborization.…”

“…Additionally, Ledderose et al [97] reported that Pcdhg knockout olfactory granule cells exhibit a near-complete lack of spines; it should be noted however that the spines in these axonless neurons are somewhat different in structure and function to the typical spines found in cortical or hippocampal neurons. In contrast to the shRNA knockdown results of Suo et al [95], Molumby et al [108] examined Pcdhg null cortical neurons in vivo and found an increase in overall spine density, primarily due to more thin spines. Consistent with this, overexpression of a single γ-Pcdh isoform (γ-Pcdh-A1) in the cortex in vivo using a Cre-activated transgenic mouse line resulted in significantly decreased overall spine density, due to reductions in mushroom and thin spines accompanied by a smaller increase in stubby spines [108].…”

“…In contrast to the shRNA knockdown results of Suo et al [95], Molumby et al [108] examined Pcdhg null cortical neurons in vivo and found an increase in overall spine density, primarily due to more thin spines. Consistent with this, overexpression of a single γ-Pcdh isoform (γ-Pcdh-A1) in the cortex in vivo using a Cre-activated transgenic mouse line resulted in significantly decreased overall spine density, due to reductions in mushroom and thin spines accompanied by a smaller increase in stubby spines [108]. Furthermore, co-expression of a γ-Pcdh isoform can inhibit the increase in spine density seen in cultured hippocampal neurons following overexpression of neuroligin-1 [108].…”

“…In cortical neurons lacking Pcdhg genes, spine density is increased in vivo; an opposite effect is seen when a single Pcdhg isoform is overexpressed in the cortex [108]. This may be due to the ability of γ-Pcdhs to bind to and inhibit the functionality of neuroligin-1 [108].…”

“…In cortical neurons lacking Pcdhg genes, spine density is increased in vivo; an opposite effect is seen when a single Pcdhg isoform is overexpressed in the cortex [108]. This may be due to the ability of γ-Pcdhs to bind to and inhibit the functionality of neuroligin-1 [108]. Similarly, a number of non-clustered Pcdhs can interact with other synaptic molecules to promote endocytosis and dendritic spine loss: Pcdh8 does this through interaction with N-cadherin [69], while Pcdh10 induces synapse elimination by interacting with ubiquitinated PSD-95 [118].…”