Activin and GDF11 collaborate in feedback control of neuroepithelial stem cell proliferation and fate
Activin and GDF11 collaborate in feedback control of neuroepithelial stem cell proliferation and fate
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DOI：
10.1242/dev.065870
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发表时间：
2011-10-01
期刊：
影响因子：
4.6
通讯作者：
Calof, Anne L.
中科院分区：
文献类型：
--
作者：
Gokoffski, Kimberly K.;Wu, Hsiao-Huei;Calof, Anne L.
嗅觉上皮模型系统的研究表明，神经元的产生受负反馈调节。先前，我们发现局部产生的信号，TGF β超家族配体GDF11，通过抑制产生嗅觉受体神经元的直接神经元前体（INPs）的增殖来调节嗅觉受体神经元的发生。GDF11可被卵泡listatin （FST）拮抗，FST也是局部产生的。在这里，我们发现Fst（-/-）小鼠表现出显著的神经发生减少，这种表型只能部分解释为GDF11活性增加。取而代之的是第二种fst结合因子，激活素。β B （ACT β B）通过一种独特的机制抑制神经发生：GDF11抑制INPs的扩增，而ACT β B抑制干细胞和早期祖细胞的扩增。我们提供的数据支持这一概念，即后一种细胞，以前被认为是两种不同的类型，构成了一个动态的干细胞/祖细胞群体，其中单个细胞交替表达Sox2和/或Ascl1。此外，我们证明ACT β B和GDF11之间的相互作用决定了干细胞/祖细胞是否采用胶质细胞还是神经元细胞的命运。总之，这些数据表明，干细胞和固定祖细胞之间的转变既不是急剧的，也不是不可逆的，并且GDF11、ACT β B和FST是控制该系统中细胞总数和神经元与胶质细胞比例的电路的关键组成部分。因此，我们的研究结果表明，参与控制组织大小的信号与那些调节不同细胞类型比例的信号之间存在密切联系。
Studies of the olfactory epithelium model system have demonstrated that production of neurons is regulated by negative feedback. Previously, we showed that a locally produced signal, the TGF beta superfamily ligand GDF11, regulates the genesis of olfactory receptor neurons by inhibiting proliferation of the immediate neuronal precursors (INPs) that give rise to them. GDF11 is antagonized by follistatin (FST), which is also produced locally. Here, we show that Fst(-/-) mice exhibit dramatically decreased neurogenesis, a phenotype that can only be partially explained by increased GDF11 activity. Instead, a second FST-binding factor, activin. beta B (ACT beta B), inhibits neurogenesis by a distinct mechanism: whereas GDF11 inhibits expansion of INPs, ACT beta B inhibits expansion of stem and early progenitor cells. We present data supporting the concept that these latter cells, previously considered two distinct types, constitute a dynamic stem/progenitor population in which individual cells alternate expression of Sox2 and/or Ascl1. In addition, we demonstrate that interplay between ACT beta B and GDF11 determines whether stem/progenitor cells adopt a glial versus neuronal fate. Altogether, the data indicate that the transition between stem cells and committed progenitors is neither sharp nor irreversible and that GDF11, ACT beta B and FST are crucial components of a circuit that controls both total cell number and the ratio of neuronal versus glial cells in this system. Thus, our findings demonstrate a close connection between the signals involved in the control of tissue size and those that regulate the proportions of different cell types.