Rewiring the retinal ganglion cell gene regulatory network: Neurod1 promotes retinal ganglion cell fate in the absence of Math5
Rewiring the retinal ganglion cell gene regulatory network: Neurod1 promotes retinal ganglion cell fate in the absence of Math5
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DOI：
10.1242/dev.024612
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发表时间：
2008-10-15
期刊：
影响因子：
4.6
通讯作者：
Klein, William H.
中科院分区：
文献类型：
--
作者：
Mao, Chai-An;Wang, Steven W.;Klein, William H.
视网膜前体细胞（Retinal progenitor cells，RPC）表达碱性螺旋-环-螺旋（basic helix-loop-helix，bHLH）因子，其时空镶嵌模式被认为有助于个体视网膜细胞身份的建立。在这里，我们要问的是，这种严格调控的模式是否是必不可少的早期视网膜细胞类型的有序分化，以及不同的bHLH基因是否有不同的功能，适应每个RPC。为了解决这些问题，我们将一个bHLH基因替换为另一个。Math 5是一种bHLH基因，对建立视网膜神经节细胞（RGC）命运至关重要。我们分析了小鼠的视网膜，其中Math 5被替换为Neurod 1或Math 3，bHLH基因在另一个RPC中表达，并需要建立无长突细胞的命运。在没有Math 5的情况下，Math 5（Neurod 1-KI）能够指定RGC，激活RGC基因并恢复视神经，尽管不如Math 5有效。相比之下，Math 5（Math 3-KI）在替代Math 5方面的效率远低于Math 5（Neurod 1-KI）。此外，来自Math 5（Neurod 1-KI/Math 3-KI）等位基因的Neurod 1和Math 3的表达不会导致增强的无长突细胞产生。这些结果是出乎意料的，因为它们表明，bHLH基因，目前被认为已经进化出高度专门化的功能，仍然能够通过解释编程到RPC谱系中的局部位置信息来调整它们的功能。我们的结论是，虽然Neurod 1和Math 3已经发展了专门的功能，建立无长突细胞的命运，他们仍然能够替代功能时，在国外的环境中表达。
Retinal progenitor cells (RPCs) express basic helix-loop-helix ( bHLH) factors in a strikingly mosaic spatiotemporal pattern, which is thought to contribute to the establishment of individual retinal cell identity. Here, we ask whether this tightly regulated pattern is essential for the orderly differentiation of the early retinal cell types and whether different bHLH genes have distinct functions that are adapted for each RPC. To address these issues, we replaced one bHLH gene with another. Math5 is a bHLH gene that is essential for establishing retinal ganglion cell (RGC) fate. We analyzed the retinas of mice in which Math5 was replaced with Neurod1 or Math3, bHLH genes that are expressed in another RPC and are required to establish amacrine cell fate. In the absence of Math5, Math5(Neurod1-KI) was able to specify RGCs, activate RGC genes and restore the optic nerve, although not as effectively as Math5. By contrast, Math5(Math3-KI) was much less effective than Math5(Neurod1-KI) in replacing Math5. In addition, expression of Neurod1 and Math3 from the Math5(Neurod1-KI/Math3-KI) allele did not result in enhanced amacrine cell production. These results were unexpected because they indicated that bHLH genes, which are currently thought to have evolved highly specialized functions, are nonetheless able to adjust their functions by interpreting the local positional information that is programmed into the RPC lineages. We conclude that, although Neurod1 and Math3 have evolved specialized functions for establishing amacrine cell fate, they are nevertheless capable of alternative functions when expressed in foreign environments.