Wnt/planar cell polarity signaling controls the anterior-posterior organization of monoaminergic axons in the brainstem.
Wnt/planar cell polarity signaling controls the anterior-posterior organization of monoaminergic axons in the brainstem.
复制标题
DOI：
10.1523/jneurosci.4508-10.2010
复制
发表时间：
2010-11-24
期刊：
影响因子：
--
通讯作者：
Pasterkamp RJ
中科院分区：
文献类型：
--
作者：
Fenstermaker AG;Prasad AA;Bechara A;Adolfs Y;Tissir F;Goffinet A;Zou Y;Pasterkamp RJ
脑干的单胺能神经元（5 -羟色胺能神经元（5HT）和多巴胺能神经元（mdDA））沿前后轴投射轴突。尽管它们具有重要的生理功能和疾病意义，但决定这些沿前后轴形成的突起的分子机制尚不清楚。在这里，我们揭示了单胺能系统的前后组织中Wnt/平面细胞极性信号的新要求。我们发现5HT和mdDA轴突表达核心平面细胞极性成分Frizzled3、Celsr3和Vangl2。此外，单胺能投射在Frizzled3、Celsr3和Vangl2突变小鼠中显示出前后导向缺陷。唯一已知的平面细胞极性信号的配体是Wnt蛋白。在培养中，Wnt5a吸引5HT但排斥mdDA轴突，而Wnt7b吸引mdDA轴突。然而，Frizzled3突变小鼠的mdDA轴突对Wnt5a和Wnt7b没有反应。两种wnt均沿前后轴呈梯度表达，这与它们作为方向线索的作用一致。最后，Wnt5a突变体在mdDA投影中表现出短暂的前后导向缺陷。此外，我们观察到迁移下行5HT神经元的细胞体最终沿其轴突方向重新定向。在Frizzled3突变体中，许多5HT和mdDA神经元细胞体沿其异常轴突投射方向异常定向。总的来说，我们的数据表明，Wnt/平面细胞极性信号可能是一种全局的前后导向机制，控制着脊髓以外的轴突和细胞组织。
Monoaminergic neurons (serotonergic (5HT) and dopaminergic (mdDA)) in the brainstem project axons along the anterior-posterior axis. Despite their important physiological functions and implication in disease, the molecular mechanisms that dictate the formation of these projections along the anterior-posterior axis remain unknown. Here we reveal a novel requirement for Wnt/planar cell polarity signaling in the anterior-posterior organization of the monoaminergic system. We find that 5HT and mdDA axons express the core planar cell polarity components Frizzled3, Celsr3 and Vangl2. In addition, monoaminergic projections show anterior-posterior guidance defects in Frizzled3, Celsr3 and Vangl2 mutant mice. The only known ligands for planar cell polarity signaling are Wnt proteins. In culture, Wnt5a attracts 5HT but repels mdDA axons and Wnt7b attracts mdDA axons. However, mdDA axons from Frizzled3 mutant mice are unresponsive to Wnt5a and Wnt7b. Both Wnts are expressed in gradients along the anterior-posterior axis, consistent with their role as directional cues. Finally, Wnt5a mutants show transient anterior-posterior guidance defects in mdDA projections. Furthermore, we observe that the cell bodies of migrating descending 5HT neurons eventually re-orient along the direction of their axons. In Frizzled3 mutants, many 5HT and mdDA neuron cell bodies are oriented abnormally along the direction of their aberrant axon projections. Overall, our data suggest that Wnt/planar cell polarity signaling may be a global anterior-posterior guidance mechanism that controls axonal and cellular organization beyond the spinal cord.