NRP1 and NRP2 cooperate to regulate gangliogenesis, axon guidance and target innervation in the sympathetic nervous system.
NRP1 and NRP2 cooperate to regulate gangliogenesis, axon guidance and target innervation in the sympathetic nervous system.
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DOI：
10.1016/j.ydbio.2012.06.026
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发表时间：
2012-09-15
影响因子：
2.7
通讯作者：
Ruhrberg, Christiana
中科院分区：
文献类型：
--
作者：
Maden, Charlotte H.;Gomes, John;Schwarz, Quenten;Davidson, Kathryn;Tinker, Andrew;Ruhrberg, Christiana
交感神经系统 (SNS) 由胚胎发育过程中的神经嵴 (NC) 细胞产生，支配脊椎动物的内脏器官以调节其应激反应。 NRP1 和 NRP2 是 3 类信号蛋白 (SEMA) 家族引导信号的受体，在交感神经核细胞及其后代中以部分重叠的模式表达。通过比较交感神经细胞系和血管内皮细胞系中缺乏 NRP1 或其配体 SEMA3A 的小鼠与缺乏 NRP1 的小鼠的表型，我们证明通过 NRP1 的 SEMA3A 信号传导在 SNS 发育中具有多种细胞自主作用。这些作用包括神经元细胞体定位、神经元聚集和轴突引导，首先在交感链组装期间，然后调节心脏和主动脉的神经支配。 NRP2或其配体SEMA3F的缺失比SEMA3A/NRP1信号传导的缺失更轻微地损害交感神经节生成，但引起沿胚胎主动脉的异位神经突延伸。对 SNS 中缺乏 SEMA3A 和 SEMA3F 或 NRP1 和 NRP2 的复合突变体的分析表明，两种信号通路协同组织 SNS。我们进一步表明，交感神经谱系中缺乏 NRP1 的小鼠交感神经发育异常会产生功能性后果，因为它会导致窦性心动过缓，类似于缺乏 SEMA3A 的小鼠。 ► NRP1 和 NRP2 在交感神经元及其前体中共表达。 ► SEMA3A 通过 NRP1 发出信号来调节交感神经节生成和轴突引导。 ► SEMA3F 通过 NRP2 发出信号来调节交感神经轴突引导。 ► SEMA3A/NRP1 和 SEMA3F/NRP2 在交感神经系统模式中协同作用。 ► NRP1 突变体中心脏的交感神经支配异常会导致心动过缓。
The sympathetic nervous system (SNS) arises from neural crest (NC) cells during embryonic development and innervates the internal organs of vertebrates to modulate their stress response. NRP1 and NRP2 are receptors for guidance cues of the class 3 semaphorin (SEMA) family and are expressed in partially overlapping patterns in sympathetic NC cells and their progeny. By comparing the phenotypes of mice lacking NRP1 or its ligand SEMA3A with mice lacking NRP1 in the sympathetic versus vascular endothelial cell lineages, we demonstrate that SEMA3A signalling through NRP1 has multiple cell-autonomous roles in SNS development. These roles include neuronal cell body positioning, neuronal aggregation and axon guidance, first during sympathetic chain assembly and then to regulate the innervation of the heart and aorta. Loss of NRP2 or its ligand SEMA3F impaired sympathetic gangliogenesis more mildly than loss of SEMA3A/NRP1 signalling, but caused ectopic neurite extension along the embryonic aorta. The analysis of compound mutants lacking SEMA3A and SEMA3F or NRP1 and NRP2 in the SNS demonstrated that both signalling pathways cooperate to organise the SNS. We further show that abnormal sympathetic development in mice lacking NRP1 in the sympathetic lineage has functional consequences, as it causes sinus bradycardia, similar to mice lacking SEMA3A. ► NRP1 and NRP2 are co-expressed in sympathetic neurons and their precursors. ► SEMA3A signals through NRP1 to regulate sympathetic gangliogenesis and axon guidance. ► SEMA3F signals through NRP2 to regulate sympathetic axon guidance. ► SEMA3A/NRP1 and SEMA3F/NRP2 act synergistically in sympathetic nervous system patterning. ► Abnormal sympathetic innervation of the heart leads to bradycardia in NRP1 mutants.
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