The adhesion-GPCR BAI1 shapes dendritic arbors via Bcr-mediated RhoA activation causing late growth arrest
The adhesion-GPCR BAI1 shapes dendritic arbors via Bcr-mediated RhoA activation causing late growth arrest
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DOI：
10.7554/elife.47566
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发表时间：
2019-08-28
期刊：
影响因子：
7.7
通讯作者：
Tolias, Kimberley F.
中科院分区：
文献类型：
--
作者：
Duman, Joseph G.;Mulherkar, Shalaka;Tolias, Kimberley F.
树突乔木结构深刻影响神经元的连接和功能，异常的树突形态是神经精神疾病的特征。在这里，我们将粘附 GPCR BAI1 确定为树突分枝的重要调节因子。小鼠或大鼠海马神经元的 BAI1 缺失会导致树突肥大，而 BAI1 过度表达会导致树突回缩。这些缺陷具体表现为枝晶从生长过渡到稳定。 BAI1 介导的生长停滞与其 Racl 依赖性突触发生功能无关。相反，BAI1 与小型 GTP 酶 RhoA 结合，驱动树突中 RhoA 的晚期激活，同时生长停滞。 BAI1 损失会降低 RhoA 激活，使其与树突动力学脱钩，导致过度生长。 BAI1 已知的下游效应器均不会介导 BAI1 依赖性生长停滞。相反，BAI1 在发育后期与 Rho-GTPase 调节蛋白 Bcr 结合，并刺激其隐秘的 RhoA-GEF 活性，该活性与其 Racl-GAP 活性一起发挥作用，终止树枝化。我们的结果揭示了介导树突发育关键转变的晚效信号通路。
Dendritic arbor architecture profoundly impacts neuronal connectivity and function, and aberrant dendritic morphology characterizes neuropsychiatric disorders. Here, we identify the adhesion-GPCR BAI1 as an important regulator of dendritic arborization. BAI1 loss from mouse or rat hippocampal neurons causes dendritic hypertrophy, whereas BAI1 overexpression precipitates dendrite retraction. These defects specifically manifest as dendrites transition from growth to stability. BAI1-mediated growth arrest is independent of its Racl-dependent synaptogenic function. Instead, BAI1 couples to the small GTPase RhoA, driving late RhoA activation in dendrites coincident with growth arrest. BAI1 loss lowers RhoA activation and uncouples it from dendrite dynamics, causing overgrowth. None of BAI1's known downstream effectors mediates BAI1-dependent growth arrest. Rather, BAI1 associates with the Rho-GTPase regulatory protein Bcr late in development and stimulates its cryptic RhoA-GEF activity, which functions together with its Racl-GAP activity to terminate arborization. Our results reveal a late-acting signaling pathway mediating a key transition in dendrite development.