Bone morphogenic protein signaling is a major determinant of dentate development.
Bone morphogenic protein signaling is a major determinant of dentate development.
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DOI：
10.1523/jneurosci.0128-13.2013
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发表时间：
2013-04-17
期刊：
影响因子：
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通讯作者：
Pleasure SJ
中科院分区：
文献类型：
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作者：
Choe Y;Kozlova A;Graf D;Pleasure SJ
为了了解齿状回 (DG) 的终生神经发生，表征齿状神经干细胞和控制其发育的信号至关重要。在本研究中，我们表明骨形态发生蛋白（Bmp）信号是胚胎齿状发育的关键调节因子，是胚胎 DG 祖细胞中启动神经发生和出生后齿状神经干细胞建立所必需的。我们测试了这样的假设：Bmp 信号传导部分通过控制 Lef1 的表达来调节齿状发育，Lef1 是一种在齿状干细胞中表达的 Wnt 响应转录因子，并且是齿状颗粒细胞产生所必需的。 Bmp 通过 Acvr1 受体激活诱导胚胎 DG 中的 Lef1 表达和神经发生。胚胎中线中 Bmp7 的异位表达增加了 DG 神经发生，而抑制局部 Bmp 信号传导则减少了胚胎 DG 神经发生。由于脑膜发育缺陷而选择性丧失 Bmp 表达或选择性条件性删除脑膜 Bmp7 的小鼠也有齿状发育缺陷。 DG 神经干细胞中 Acvr1 或 Smad4（Bmp 信号传导的下游靶核效应子）的条件性缺失会导致出生后颗粒下区 (SGZ) 缺陷并减少神经发生。这些结果表明Acvr1介导的脑膜Bmp信号传导调节齿状中的Lef1表达，调节胚胎DG神经发生、DG神经干细胞生态位的形成和维持。
To understand life-long neurogenesis in the dentate gyrus (DG), characterizing dentate neural stem cells and the signals controlling their development are crucial. In the present study, we show that bone morphogenic protein (Bmp) signaling is a critical regulator of embryonic dentate development, required for initiating neurogenesis in embryonic DG progenitors and required for the establishment of dentate neural stem cells postnatally. We tested the hypothesis that Bmp signaling regulates dentate development in part by controlling the expression of Lef1, a Wnt responsive transcription factor expressed in dentate stem cells and absolutely required for dentate granule cell production. Bmp activation through the Acvr1 receptor induced Lef1 expression and neurogenesis in the embryonic DG. Ectopic expression of Bmp7 in the embryonic midline increased DG neurogenesis and inhibition of local Bmp signaling decreased embryonic DG neurogenesis. Mice with selective loss of Bmp expression due to defective meningeal development or with selective conditional deletion of meningeal Bmp7 also have dentate developmental defects. Conditional deletion of Acvr1 or Smad4 (a downstream target nuclear effector of Bmp signaling) in DG neural stem cells resulted in defects in the postnatal subgranular zone (SGZ) and reduced neurogenesis. These results suggest that Acvr1 mediated meningeal Bmp signaling regulates Lef1 expression in the dentate, regulating embryonic DG neurogenesis, DG neural stem cell niche formation and maintenance.