Precise Somatotopic Thalamocortical Axon Guidance Depends on LPA-Mediated PRG-2/Radixin Signaling.
Precise Somatotopic Thalamocortical Axon Guidance Depends on LPA-Mediated PRG-2/Radixin Signaling.
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DOI：
10.1016/j.neuron.2016.08.035
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发表时间：
2016-10-05
期刊：
影响因子：
16.2
通讯作者：
Vogt J
中科院分区：
文献类型：
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作者：
Cheng J;Sahani S;Hausrat TJ;Yang JW;Ji H;Schmarowski N;Endle H;Liu X;Li Y;Böttche R;Radyushkin K;Maric HM;Hoerder-Suabedissen A;Molnár Z;Prouvot PH;Trimbuch T;Ninnemann O;Huai J;Fan W;Visentin B;Sabbadini R;Strømgaard K;Stroh A;Luhmann HJ;Kneussel M;Nitsch R;Vogt J
丘脑桶状体与其相应的皮质桶的精确连接对于触须感觉信息的处理至关重要。在这里，我们表明，PRG-2，磷脂相互作用的分子，是重要的丘脑皮质轴突的指导。在PRG-2完全敲除（KO）和丘脑特异性KO小鼠中，发育中的丘脑皮质纤维过早进入皮质板，最终支配非相应的桶。这种错误的路由依赖于失去轴突对溶血磷脂酸（LPA）的敏感性，这未能击退PRG-2缺乏丘脑皮质纤维。PRG-2−/−丘脑中的PRG-2电穿孔恢复了异常的皮质神经支配。我们确定了根蛋白作为PRG-2的相互作用伙伴，并表明根蛋白在生长锥中的积累及其LPA依赖性磷酸化依赖于其与PRG-2的C-末端区域内的特定区域的结合。体内记录和胡须特异性行为测试证明PRG-2−/−动物的感觉辨别缺陷。我们的数据表明，生物活性磷脂和PRG-2是至关重要的指导丘脑轴突到其适当的皮质目标。生长锥中的PRG-2介导丘脑皮质纤维的轴突LPA敏感性生长锥中的LPA/PRG-2/RDX信号传导是一种新的轴突导向机制PRG-2缺陷破坏丘脑皮质躯体适应性的精确性PRG-2−/−小鼠改变了丘脑皮质靶向和特定的感觉缺陷。描述了一种新的轴突导向机制，依赖于丘脑皮质轴突生长锥处的PRG-2和皮质板下方合成的细胞外LPA。分子分析显示，LPA/PRG-2/RDX信号在生长锥重要的丘脑皮质靶向。
Precise connection of thalamic barreloids with their corresponding cortical barrels is critical for processing of vibrissal sensory information. Here, we show that PRG-2, a phospholipid-interacting molecule, is important for thalamocortical axon guidance. Developing thalamocortical fibers both in PRG-2 full knockout (KO) and in thalamus-specific KO mice prematurely entered the cortical plate, eventually innervating non-corresponding barrels. This misrouting relied on lost axonal sensitivity toward lysophosphatidic acid (LPA), which failed to repel PRG-2-deficient thalamocortical fibers. PRG-2 electroporation in the PRG-2−/− thalamus restored the aberrant cortical innervation. We identified radixin as a PRG-2 interaction partner and showed that radixin accumulation in growth cones and its LPA-dependent phosphorylation depend on its binding to specific regions within the C-terminal region of PRG-2. In vivo recordings and whisker-specific behavioral tests demonstrated sensory discrimination deficits in PRG-2−/− animals. Our data show that bioactive phospholipids and PRG-2 are critical for guiding thalamic axons to their proper cortical targets. PRG-2 at the growth cone mediates axonal LPA sensitivity of thalamocortical fibers LPA/PRG-2/RDX signaling in the growth cone is a novel axon guidance mechanism PRG-2 deficiency disrupts precision of thalamocotrical somatotopy PRG-2−/− mice have altered thalamocortical targeting and specific sensory defects Cheng et al. describe a new axon guidance mechanism depending on PRG-2 at the growth cone of thalamocortical axons and extracellular LPA synthesized below the cortical plate. Molecular analysis revealed LPA/PRG-2/RDX signaling at the growth cone important for thalamocortical targeting.