Tlx3 and Tlx1 are post-mitotic selector genes determining glutamatergic over GABAergic cell fates
Tlx3 and Tlx1 are post-mitotic selector genes determining glutamatergic over GABAergic cell fates
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DOI：
10.1038/nn1221
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发表时间：
2004-05-01
影响因子：
25
通讯作者：
Ma, QF
中科院分区：
文献类型：
--
作者：
Cheng, LP;Arata, A;Ma, QF
在脊椎动物神经系统中，谷氨酸能和GABA能神经元分别介导大部分兴奋性和抑制性神经传递。发育中的神经元在这两种细胞命运之间进行选择的过程知之甚少。在这里，我们表明，同源异型盒基因Tlx 3和Tlx 1决定兴奋抑制细胞的命运在小鼠脊髓背侧。首先，我们发现，Tlx 3是所需的规格，并表示，mammatergic神经元。通用的和区域特异性的amatergic标记，包括VGLUT 2和AMPA受体Gria 2，Tlx突变体背角中不存在。第二，脊髓GABA能标记物在Tlx突变体中被去抑制，包括GABA能分化所必需的Pax 2、调节GABA合成和转运的Gad 1/2和Viaat以及红藻氨酸受体Grik 2/3。第三，Tlx 3的异位表达足以抑制GABA能神经元的分化并诱导GABA能神经元的形成。最后，过多的GABA介导的抑制导致Tlx 3突变小鼠中枢呼吸回路功能障碍。
Glutamatergic and GABAergic neurons mediate much of the excitatory and inhibitory neurotransmission, respectively, in the vertebrate nervous system. The process by which developing neurons select between these two cell fates is poorly understood. Here we show that the homeobox genes Tlx3 and Tlx1 determine excitatory over inhibitory cell fates in the mouse dorsal spinal cord. First, we found that Tlx3 was required for specification of, and expressed in, glutamatergic neurons. Both generic and region-specific glutamatergic markers, including VGLUT2 and the AMPA receptor Gria2, were absent in Tlx mutant dorsal horn. Second, spinal GABAergic markers were derepressed in Tlx mutants, including Pax2 that is necessary for GABAergic differentiation, Gad1/2 and Viaat that regulate GABA synthesis and transport, and the kainate receptors Grik2/3. Third, ectopic expression of Tlx3 was sufficient to suppress GABAergic differentiation and induce formation of glutamatergic neurons. Finally, excess GABA-mediated inhibition caused dysfunction of central respiratory circuits in Tlx3 mutant mice.