Neuregulin repellent signaling via ErbB4 restricts GABAergic interneurons to migratory paths from ganglionic eminence to cortical destinations.
Neuregulin repellent signaling via ErbB4 restricts GABAergic interneurons to migratory paths from ganglionic eminence to cortical destinations.
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DOI：
10.1186/1749-8104-7-10
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发表时间：
2012-02-29
影响因子：
3.6
通讯作者：
O'Leary DD
中科院分区：
文献类型：
--
作者：
Li H;Chou SJ;Hamasaki T;Perez-Garcia CG;O'Leary DD
皮层GABA能中间神经元（IN）产生于内侧神经节隆起（MGE），并切向迁移到皮层。因为大多数（如果不是全部）迁移MGE衍生的IN表达神经调节蛋白（NRG）受体ErbB 4，我们研究了Nrg 1亚型和Nrg 3对IN迁移通过腹侧端脑（vTel）和皮质内的影响。在IN迁移过程中，NRG表达结构域和ErbB 4表达的分布，MGE衍生的IN是互补的，在vTel和皮质中都有最小的重叠。在野生型小鼠中，在NRG表达的区域内，这些IN集中在低或不存在NRG表达的位置。然而，在ErbB 4-/-HER 4心脏突变小鼠中，IN缺乏ErbB 4，这些互补模式被降解，IN分布和NRG表达结构域之间存在明显的重叠。这些发现表明，NRG是迁移ErbB 4表达的IN的驱避剂，这一功能得到了体外和体内实验的支持。首先，在胶原共培养物中，MGE衍生的细胞优先迁移远离分泌的NRG的来源。第二，从野生型胚胎小鼠的活前脑切片上的野生型MGE外植体迁移的细胞倾向于避免内源性NRG表达结构域，而从MGE外植体迁移的ErbB 4缺陷细胞没有表现出这种避免行为，相反，它们具有更均匀分布的放射状图案。第三，异位NRG表达在子宫内电穿孔产生的IN迁移通路中阻断IN迁移，并导致阻断远端的皮质基本上没有INs. Finally，更少的IN到达ErbB 4突变体的皮质，表明NRG-ErbB 4信号传导是指导IN从MGE迁移到皮质所必需的。我们的研究结果表明，NRG作为迁移ErbB 4表达，MGE衍生的GABA能IN的排斥剂，并且NRG的模式化表达漏斗IN，因为它们从MGE迁移到它们的皮质目的地。
Cortical GABAergic interneurons (INs) are generated in the medial ganglionic eminence (MGE) and migrate tangentially into cortex. Because most, if not all, migrating MGE-derived INs express the neuregulin (NRG) receptor, ErbB4, we investigated influences of Nrg1 isoforms and Nrg3 on IN migration through ventral telencephalon (vTel) and within cortex. During IN migration, NRG expression domains and distributions of ErbB4-expressing, MGE-derived INs are complementary with minimal overlap, both in vTel and cortex. In wild-type mice, within fields of NRG expression, these INs are focused at positions of low or absent NRG expression. However, in ErbB4-/- HER4heart mutant mice in which INs lack ErbB4, these complementary patterns are degraded with considerable overlap evident between IN distribution and NRG expression domains. These findings suggest that NRGs are repellents for migrating ErbB4-expressing INs, a function supported by in vitro and in vivo experiments. First, in collagen co-cultures, MGE-derived cells preferentially migrate away from a source of secreted NRGs. Second, cells migrating from wild-type MGE explants on living forebrain slices from wild-type embryonic mice tend to avoid endogenous NRG expression domains, whereas this avoidance behavior is not exhibited by ErbB4-deficient cells migrating from MGE explants and instead they have a radial pattern with a more uniform distribution. Third, ectopic NRG expression in the IN migration pathway produced by in utero electroporation blocks IN migration and results in cortex distal to the blockade being largely devoid of INs. Finally, fewer INs reach cortex in ErbB4 mutants, indicating that NRG-ErbB4 signaling is required for directing IN migration from the MGE to cortex. Our results show that NRGs act as repellents for migrating ErbB4-expressing, MGE-derived GABAergic INs and that the patterned expression of NRGs funnels INs as they migrate from the MGE to their cortical destinations.
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