Neurogenin2 expression together with NeuroM regulates GDNF family neurotrophic factor receptor α1 (GFRα1) expression in the embryonic spinal cord.
Neurogenin2 expression together with NeuroM regulates GDNF family neurotrophic factor receptor α1 (GFRα1) expression in the embryonic spinal cord.
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DOI：
10.1016/j.ydbio.2012.08.002
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发表时间：
2012-10
影响因子：
2.7
通讯作者：
T. Shimada;H. Yaginuma;Noboru Sato;S. Homma
中科院分区：
文献类型：
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作者：
T. Shimada;H. Yaginuma;Noboru Sato;S. Homma
在神经系统的许多区域，转录因子的组合作用决定了神经元亚型的个体命运。相反，我们报告了一个单一的转录因子控制不同亚型神经元共有的表型，即脊髓中神经营养因子受体的表达。在鸡胚胎脊髓背腹轴，胶质细胞源性神经营养因子受体(GDNF1：GFRNGN1)家族的表达与两种碱性螺旋-环-螺旋(α)转录因子(Neurom和Neurogenin2：α2)的表达模式有关。在鸡胚胎的卵内电穿孔实验表明，单独的神经细胞的过度表达足以诱导异位的GFRGFRα1的表达，而不存在明显的神经元分化，而神经活动的抑制则导致GFRGFRα1表达的特异性丢失，提示神经细胞可能是GFRGFRα1表达的分化因子。NGN2的过度表达也足以诱导性早熟GFRα1的表达。然而，强制表达专性抑制型和激活型NGN2也可诱导α-1的异常表达。因此，任何偏离NGN2表达的最佳水平都会导致GfRα1的异常表达。与此一致的是，其他bHLH因子对NGN2表达水平的控制也导致了肾小球滤泡生长因子受体α1的异位表达。例如，Ascl1的下调和Ptf1a的上调诱导了GFRα1的异位表达，而与Ascl1和Ptf1a(Ascl1/Ptf1)在脊髓中的内源性表达模式无关。Ascl1/Ptf1a活性被抑制后，即使在Ascl1/Ptf1a阴性区域，NGN2和GFRα1的表达也被取消。这些数据表明，GFRα1表达的决定因素存在一个独特的调控序列，其中Ascl1/Ptf1a可能竞争性地干预，随机调节默认的Ngn2表达水平。因此，NGN2和NERM一起作为读数来调节GFRα1的表达，这种表达存在于多种亚型的脊髓神经元中。
In many regions of the nervous system, the combinatorial action of transcriptional factors specifies the individual fate of neuronal subtypes. Contrary to this, we report that a single transcriptional factor controls a phenotype shared by different subtypes of neurons, namely the expression of a neurotrophic factor receptor in the spinal cord. Along the dorsoventral axis of the chick embryo spinal cord, the expression pattern of a specific receptor for glial cell line derived-neurotrophic factor (GDNF family of receptors α1: GFRα1) was related to that of two basic helix-loop-helix (bHLH) transcriptional factors (NeuroM and Neurogenin2: Ngn2). In ovo electroporation in the chick embryo revealed that the overexpression of NeuroM alone was sufficient to induce ectopic GFRα1 expression without overt neuronal differentiation, whereas the suppression of NeuroM activity resulted in the specific loss of GFRα1 expression, indicating that NeuroM may act as a differentiation factor for GFRα1 expression. Ngn2 overexpression was also sufficient to induce precocious GFRα1 expression. However, the forced expression of both obligate suppressor and activator forms of Ngn2 also induced aberrant GFRα1 expression. Thus, any deviation from an optimum level of Ngn2 expression resulted in aberrant GFRα1 expression. Consistent with this, manipulation of Ngn2 expression levels by other bHLH factors also resulted in ectopic GFRα1 expression. For example, the downregulation by Ascl1 and the upregulation by Ptf1a induced ectopic GFRα1 expression, irrespective of endogenous expression patterns of Ascl1 and Ptf1a (Ascl1/Ptf1) in the spinal cord. The suppression of Ascl1/Ptf1a activities abolished Ngn2 and GFRα1 expression, even in Ascl1/Ptf1a-negative regions. These data indicate the presence of a distinct regulatory sequence for a determinant of GFRα1 expression, in which Ascl1/Ptf1a may competitively intervene to stochastically modulate default Ngn2 expression levels. Thus, Ngn2 together with NeuroM serves as readout to regulate GFRα1 expression, which occurs in multiple subtypes of spinal neurons.