Foxg1 promotes olfactory neurogenesis by antagonizing Gdf11
Foxg1 promotes olfactory neurogenesis by antagonizing Gdf11
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DOI：
10.1242/dev.034967
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发表时间：
2009-05-01
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：
Kawauchi, Shimako;Kim, Joon;Calof, Anne L.
Foxg 1是一种翼状螺旋转录因子，可促进前部神经结构的发育;在缺乏Foxg 1的小鼠中，大脑半球和嗅上皮（OE）的发育严重减少。已经表明，Foxg 1通过正向调节支持神经发生的生长因子如Fgf 8的表达而起作用。然而，Foxg 1也结合Smad转录复合物，使其能够负调节TGF β家族配体的作用。在这里，我们提供的证据表明，后者的影响解释了Foxg 1的能力，以驱动神经发生的OE。我们表明，Foxg 1是在发展中的OE在同一时间表达的基因编码的生长分化因子11（Gdf 11），TGF β家族成员，介导的负反馈控制OE神经发生。Gdf 11突变在相当程度上挽救了Foxg 1（-/-）OE的主要缺陷，包括神经前体和嗅觉受体神经元的早期严重丧失，以及随后的神经发生和鼻腔形成的崩溃。拯救是基因剂量依赖性的，即使Gdf 11的一个等位基因的丢失也会恢复大量的神经发生。值得注意的是，我们没有发现Fgf 8在Foxg 1（-/-）OE中表达中断的证据。然而，我们确实观察到卵泡抑素（Fst）（其编码通常在OE中及其周围表达的分泌型Gdf 11拮抗剂）表达失败，以及这些突变体中剩余OE中Gdf 11自身表达增加。Fst表达在Foxg 1（-/-）; Gdf 11（-/-）和Foxg 1（-/-）; Gdf 11（+/-）小鼠中得到拯救。这些数据表明Foxg 1对Gdf 11介导的神经发生负反馈的影响可能是直接和间接的。此外，Foxg 1-/-小鼠大脑半球发育缺陷并不能通过Gdf 11突变来挽救，Gdf 11在这些结构中也没有高水平表达。因此，Foxg 1的促神经原性作用可能通过神经系统不同部位的不同信号通路介导。
Foxg1, a winged-helix transcription factor, promotes the development of anterior neural structures; in mice lacking Foxg1, development of the cerebral hemispheres and olfactory epithelium (OE) is severely reduced. It has been suggested that Foxg1 acts by positively regulating the expression of growth factors, such as Fgf8, which support neurogenesis. However, Foxg1 also binds Smad transcriptional complexes, allowing it to negatively regulate the effects of TGF beta family ligands. Here, we provide evidence that this latter effect explains much of the ability of Foxg1 to drive neurogenesis in the OE. We show that Foxg1 is expressed in developing OE at the same time as the gene encoding growth differentiation factor 11 (Gdf11), a TGF beta family member that mediates negative-feedback control of OE neurogenesis. Mutations in Gdf11 rescue, to a considerable degree, the major defects in Foxg1(-/-) OE, including the early, severe loss of neural precursors and olfactory receptor neurons, and the subsequent collapse of both neurogenesis and nasal cavity formation. Rescue is gene-dosage dependent, with loss of even one allele of Gdf11 restoring substantial neurogenesis. Notably, we find no evidence for a disruption of Fgf8 expression in Foxg1(-/-) OE. However, we do observe both a failure of expression of follistatin (Fst), which encodes a secreted Gdf11 antagonist normally expressed in and around OE, and an increase in the expression of Gdf11 itself within the remaining OE in these mutants. Fst expression is rescued in Foxg1(-/-);Gdf11(-/-) and Foxg1(-/-);Gdf11(+/-) mice. These data suggest that the influence of Foxg1 on Gdf11-mediated negative feedback of neurogenesis may be both direct and indirect. In addition, defects in development of the cerebral hemispheres in Foxg1-/- mice are not rescued by mutations in Gdf11, nor is Gdf11 expressed at high levels within these structures. Thus, the pro-neurogenic effects of Foxg1 are likely to be mediated through different signaling pathways in different parts of the nervous system.