Department of Neurology, Programs in Neuroscience and Developmental Stem Cell Biology, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California 94158, USA.
J Neurosci. 2013 Apr 17;33(16):6766-75. doi: 10.1523/JNEUROSCI.0128-13.2013.
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 Activin receptor type I (Acvr1) or Smad4 (a downstream target nuclear effector of Bmp signaling) in DG neural stem cells resulted in defects in the postnatal subgranular zone 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.
为了理解齿状回(DG)中的终身神经发生,对齿状神经干细胞的特征和控制其发育的信号进行描述是至关重要的。在本研究中,我们表明骨形态发生蛋白(Bmp)信号是胚胎 DG 祖细胞神经发生的关键调节因子,对于胚胎 DG 祖细胞中的神经发生和出生后 DG 神经干细胞的建立都是必需的。我们检验了以下假说:Bmp 信号通过控制 Lef1 的表达来调节 DG 的发育,Lef1 是一种在 DG 干细胞中表达的 Wnt 反应转录因子,对于 DG 颗粒细胞的产生是绝对必需的。通过 Acvr1 受体激活 Bmp 会诱导胚胎 DG 中的 Lef1 表达和神经发生。在胚胎中线异位表达 Bmp7 会增加 DG 的神经发生,而局部 Bmp 信号的抑制会减少胚胎 DG 的神经发生。由于脑膜发育缺陷或脑膜 Bmp7 选择性缺失而导致 Bmp 表达缺失的小鼠也具有 DG 发育缺陷。DG 神经干细胞中激活素受体 I(Acvr1)或 Smad4(Bmp 信号的下游核效应物)的条件性缺失会导致出生后颗粒下层区的缺陷和神经发生减少。这些结果表明,Acvr1 介导的脑膜 Bmp 信号通过调节 Lef1 在 DG 中的表达,调节胚胎 DG 神经发生、DG 神经干细胞龛形成和维持。