Signaling through BMPR-IA Regulates Quiescence and Long-Term Activity of Neural Stem Cells in the Adult Hippocampus
Signaling through BMPR-IA Regulates Quiescence and Long-Term Activity of Neural Stem Cells in the Adult Hippocampus
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DOI：
10.1016/j.stem.2010.04.016
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发表时间：
2010-07-02
期刊：
影响因子：
23.9
通讯作者：
Gage, Fred H.
中科院分区：
文献类型：
--
作者：
Mira, Helena;Andreu, Zoraida;Gage, Fred H.
成年海马体中的神经干细胞很少分裂，调节其静止的分子在很大程度上是未知的。在这里，我们表明，骨形态发生蛋白（BMP）信号是活跃的海马神经干细胞，下游的BMPR-IA。BMP可逆地减少培养的NSC的增殖，同时维持其未分化状态。在体内，通过脑内输注Noggin在海马中急性阻断BMP信号传导首先将静止的NSC招募到周期中并增加神经发生;随后，它导致干细胞分裂减少以及前体和新生神经元的耗尽。一致的是，选择性消融Bmpr 1a在海马神经干细胞，或失活的BMP典型信号在条件Smad 4敲除小鼠，短暂地增强增殖，但后来导致前体的数量减少，从而限制神经元的诞生。因此，需要BMP来平衡NSC静止/增殖，并防止支持成熟海马中连续神经发生的干细胞活性的丧失。
Neural stem cells (NSCs) in the adult hippocampus divide infrequently, and the molecules that modulate their quiescence are largely unknown. Here, we show that bone morphogenetic protein (BMP) signaling is active in hippocampal NSCs, downstream of BMPR-IA. BMPs reversibly diminish proliferation of cultured NSCs while maintaining their undifferentiated state. In vivo, acute blockade of BMP signaling in the hippocampus by intracerebral infusion of Noggin first recruits quiescent NSCs into the cycle and increases neurogenesis; subsequently, it leads to decreased stem cell division and depletion of precursors and newborn neurons. Consistently, selective ablation of Bmpr1a in hippocampal NSCs, or inactivation of BMP canonical signaling in conditional Smad4 knockout mice, transiently enhances proliferation but later leads to a reduced number of precursors, thereby limiting neuronal birth. BMPs are therefore required to balance NSC quiescence/proliferation and to prevent loss of the stem cell activity that supports continuous neurogenesis in the mature hippocampus.