F3/contactin and TAG1 play antagonistic roles in the regulation of sonic hedgehog-induced cerebellar granule neuron progenitor proliferation
F3/contactin and TAG1 play antagonistic roles in the regulation of sonic hedgehog-induced cerebellar granule neuron progenitor proliferation
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DOI：
10.1242/dev.051912
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发表时间：
2011-02-01
期刊：
影响因子：
4.6
通讯作者：
Furley, Andrew J. W.
中科院分区：
文献类型：
--
作者：
Xenaki, Dia;Martin, Indira B.;Furley, Andrew J. W.
音刺猬（SHH）通路的调节是小脑形态发生的关键因素。颗粒神经元祖细胞（GNP）增殖的刺激是SHH信号传导的中心功能，但如何局部控制尚不清楚。我们发现，两个连续表达的成员接触蛋白（CNTN）家族的粘附分子，TAG 1和F3，拮抗作用，以控制SHH诱导的增殖：F3抑制SHH诱导的GNP增殖和诱导分化，而TAG 1拮抗F3。TAG 1缺失小鼠中GNP的产生延迟并减少。F3和TAG 1与相关的L1样粘附分子NrCAM共定位于GNP上，并且F3未能抑制SHH诱导的NrCAM缺陷的GNP的增殖。我们发现，F3和SHH都主要影响一组中间GNP（IP），虽然积极分裂，也表达与分化相关的分子，包括β-微管蛋白III（TuJ 1）和TAG 1。在体内，中间祖细胞在外胚层（mEGL）的中间形成离散层，而F3在有丝分裂后颗粒神经元的轴突上表达，因为它们离开内EGL（iEGL）。因此，我们认为F3在iEGL中充当局部信号，诱导上覆mEGL中SHH刺激的细胞退出细胞周期并分化。相比之下，TAG 1在GNP上的表达拮抗mEGL中的该信号，防止过早分化并以旁分泌方式维持GNP扩增。总之，这些研究结果表明，CNTN和L1样蛋白在调节SHH诱导的神经元前体细胞增殖中起着重要作用。
Modulation of the sonic hedgehog (SHH) pathway is a crucial factor in cerebellar morphogenesis. Stimulation of granule neuron progenitor (GNP) proliferation is a central function of SHH signalling, but how this is controlled locally is not understood. We show that two sequentially expressed members of the contactin (CNTN) family of adhesion molecules, TAG1 and F3, act antagonistically to control SHH-induced proliferation: F3 suppresses SHH-induced GNP proliferation and induces differentiation, whereas TAG1 antagonises F3. Production of GNPs in TAG1-null mice is delayed and reduced. F3 and TAG1 colocalise on GNPs with the related L1-like adhesion molecule NrCAM, and F3 fails to suppress the SHH-induced proliferation of NrCAM-deficient GNPs. We show that F3 and SHH both primarily affect a group of intermediate GNPs (IPs), which, though actively dividing, also express molecules associated with differentiation, including beta-tubulin III (TuJ1) and TAG1. In vivo, intermediate progenitors form a discrete layer in the middle of the external germinal layer (mEGL), while F3 becomes expressed on the axons of postmitotic granule neurons as they leave the inner EGL (iEGL). We propose, therefore, that F3 acts as a localised signal in the iEGL that induces SHH-stimulated cells in the overlying mEGL to exit cell cycle and differentiate. By contrast, expression of TAG1 on GNPs antagonises this signal in the mEGL, preventing premature differentiation and sustaining GNP expansion in a paracrine fashion. Together, these findings indicate that CNTN and L1-like proteins play a significant role in modulating SHH-induced neuronal precursor proliferation.