γ-Protocadherins Interact with Neuroligin-1 and Negatively Regulate Dendritic Spine Morphogenesis.
γ-Protocadherins Interact with Neuroligin-1 and Negatively Regulate Dendritic Spine Morphogenesis.
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DOI：
10.1016/j.celrep.2017.02.060
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发表时间：
2017-03-14
期刊：
影响因子：
8.8
通讯作者：
Weiner JA
中科院分区：
文献类型：
--
作者：
Molumby MJ;Anderson RM;Newbold DJ;Koblesky NK;Garrett AM;Schreiner D;Radley JJ;Weiner JA
22 γ-原钙粘蛋白（γ-Pcdh）细胞粘附分子对大脑皮层复杂树突乔木的形成至关重要。在这里，我们提供的证据表明，γ-Pcdhs通过抑制突触后细胞粘附分子神经素-1 （Nlg1）负性调节突触发育。前脑缺乏所有γ-Pcdh亚型的小鼠体内树突棘密度显著增加，而过表达22种γ-Pcdh亚型之一的小鼠脊柱密度显著降低。γ-Pcdhs共表达可抑制Nlg1增加脊柱密度和诱导海马神经元突触前分化的能力。γ-Pcdhs在体外和体内均与Nlg1发生顺式物理相互作用，我们提供的证据表明，这破坏了Nlg1与其突触前伙伴neurexin1β的结合。结合先前的工作，这些数据确定了γ-Pcdhs在发育中的大脑中协调树突乔木生长和脊柱成熟复杂性的机制。Molumby等人利用条件突变和过表达小鼠细胞系，证明γ-原钙粘蛋白在体内负向调节皮质树突棘的形态发生。在体外实验中，γ-原钙粘蛋白与神经素-1相互作用，抑制其结合神经素-1 β的能力，促进突触前分化，增加海马神经元树突棘密度。
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. 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.