Lmx1b is required for the glutamatergic fates of a subset of spinal cord neurons.
Lmx1b is required for the glutamatergic fates of a subset of spinal cord neurons.
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DOI：
10.1186/s13064-016-0070-1
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发表时间：
2016-08-23
影响因子：
3.6
通讯作者：
Lewis KE
中科院分区：
文献类型：
--
作者：
Hilinski WC;Bostrom JR;England SJ;Juárez-Morales JL;de Jager S;Armant O;Legradi J;Strähle U;Link BA;Lewis KE
特定神经元的神经递质表型的改变可导致中枢神经系统（CNS）中兴奋和抑制的失衡，从而导致疾病。因此，神经递质表型的正确规范和维护至关重要。与其他神经元特性一样，神经递质表型通常由特定的转录因子指定和维持。然而，调节神经递质表型的特定分子机制和转录因子仍然在很大程度上未知。本论文利用单突变体、双突变体和转基因斑马鱼胚胎研究Lmx 1ba和Lmx 1bb在脊髓中间神经元神经递质表型调控中的作用。我们证明，lmx 1ba和lmx 1bb都在斑马鱼脊髓中表达，lmx 1bb由V0 v细胞和dI 5细胞表达。我们的功能分析表明，这些转录因子是不需要的神经递质的命运规范在早期的发展阶段，但在胚胎中至少有两个lmx 1ba和/或lmx 1bb突变等位基因有一个兴奋性（mammatergic）脊髓中间神经元的数量减少在发展的后期阶段。相反，V0 v或dI 5细胞的数量没有变化。这些数据表明，表达lmx 1b的脊髓神经元仍然正常形成，但至少有一部分失去或不形成正常的兴奋性命运。由于多巴胺能细胞的减少只在发育的后期出现，Lmx 1b可能是维持多巴胺能命运或指定后来形成的神经元子集的多巴胺能表型所必需的。使用双标记实验，我们还表明，至少有一些细胞失去了正常的谷氨酸能表型是V0 v细胞。最后，我们还建立了Evx 1和Evx 2，两个转录因子所需的V0 v细胞获得其兴奋性神经递质表型，也需要lmx 1ba和lmx 1bb在这些细胞中的表达，这表明Lmx 1ba和Lmx 1bb行为下游的Evx 1和Evx 2在V0 v细胞。Lmx 1ba和Lmx 1bb功能至少部分冗余的脊髓和三个功能lmx 1b等位基因是必需的斑马鱼在以后的发展阶段的兴奋性脊髓中间神经元的正确数量。总之，我们的数据显着增强了我们的理解脊髓神经递质的命运是如何调节的。
Alterations in neurotransmitter phenotypes of specific neurons can cause imbalances in excitation and inhibition in the central nervous system (CNS), leading to diseases. Therefore, the correct specification and maintenance of neurotransmitter phenotypes is vital. As with other neuronal properties, neurotransmitter phenotypes are often specified and maintained by particular transcription factors. However, the specific molecular mechanisms and transcription factors that regulate neurotransmitter phenotypes remain largely unknown. In this paper we use single mutant, double mutant and transgenic zebrafish embryos to elucidate the functions of Lmx1ba and Lmx1bb in the regulation of spinal cord interneuron neurotransmitter phenotypes. We demonstrate that lmx1ba and lmx1bb are both expressed in zebrafish spinal cord and that lmx1bb is expressed by both V0v cells and dI5 cells. Our functional analyses demonstrate that these transcription factors are not required for neurotransmitter fate specification at early stages of development, but that in embryos with at least two lmx1ba and/or lmx1bb mutant alleles there is a reduced number of excitatory (glutamatergic) spinal interneurons at later stages of development. In contrast, there is no change in the numbers of V0v or dI5 cells. These data suggest that lmx1b-expressing spinal neurons still form normally, but at least a subset of them lose, or do not form, their normal excitatory fates. As the reduction in glutamatergic cells is only seen at later stages of development, Lmx1b is probably required either for the maintenance of glutamatergic fates or to specify glutamatergic phenotypes of a subset of later forming neurons. Using double labeling experiments, we also show that at least some of the cells that lose their normal glutamatergic phenotype are V0v cells. Finally, we also establish that Evx1 and Evx2, two transcription factors that are required for V0v cells to acquire their excitatory neurotransmitter phenotype, are also required for lmx1ba and lmx1bb expression in these cells, suggesting that Lmx1ba and Lmx1bb act downstream of Evx1 and Evx2 in V0v cells. Lmx1ba and Lmx1bb function at least partially redundantly in the spinal cord and three functional lmx1b alleles are required in zebrafish for correct numbers of excitatory spinal interneurons at later developmental stages. Taken together, our data significantly enhance our understanding of how spinal cord neurotransmitter fates are regulated.