Mao Chai-An, Kiyama Takae, Pan Ping, Furuta Yasuhide, Hadjantonakis Anna-Katerina, Klein William H
Department of Biochemistry and Molecular Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Development. 2008 Jan;135(2):271-80. doi: 10.1242/dev.009688. Epub 2007 Dec 12.
The mechanisms regulating retinal ganglion cell (RGC) development are crucial for retinogenesis and for the establishment of normal vision. However, these mechanisms are only vaguely understood. RGCs are the first neuronal lineage to segregate from pluripotent progenitors in the developing retina. As output neurons, RGCs display developmental features very distinct from those of the other retinal cell types. To better understand RGC development, we have previously constructed a gene regulatory network featuring a hierarchical cascade of transcription factors that ultimately controls the expression of downstream effector genes. This has revealed the existence of a Pou domain transcription factor, Pou4f2, that occupies a key node in the RGC gene regulatory network and that is essential for RGC differentiation. However, little is known about the genes that connect upstream regulatory genes, such as Pou4f2 with downstream effector genes responsible for RGC differentiation. The purpose of this study was to characterize the retinal function of eomesodermin (Eomes), a T-box transcription factor with previously unsuspected roles in retinogenesis. We show that Eomes is expressed in developing RGCs and is a mediator of Pou4f2 function. Pou4f2 directly regulates Eomes expression through a cis-regulatory element within a conserved retinal enhancer. Deleting Eomes in the developing retina causes defects reminiscent of those in Pou4f2(-/-) retinas. Moreover, myelin ensheathment in the optic nerves of Eomes(-/-) embryos is severely impaired, suggesting that Eomes regulates this process. We conclude that Eomes is a crucial regulator positioned immediately downstream of Pou4f2 and is required for RGC differentiation and optic nerve development.
调节视网膜神经节细胞（RGC）发育的机制对于视网膜发生和正常视觉的建立至关重要。然而，这些机制目前仅得到模糊的了解。RGC是发育中的视网膜中第一个从多能祖细胞分离出来的神经元谱系。作为输出神经元，RGC表现出与其他视网膜细胞类型截然不同的发育特征。为了更好地理解RGC的发育，我们之前构建了一个基因调控网络，其特征是转录因子的分层级联，最终控制下游效应基因的表达。这揭示了一种Pou结构域转录因子Pou4f2的存在，它在RGC基因调控网络中占据关键节点，并且对RGC分化至关重要。然而，对于连接上游调控基因（如Pou4f2）与负责RGC分化的下游效应基因的基因了解甚少。本研究的目的是表征胚外中胚层决定因子（Eomes）的视网膜功能，Eomes是一种T盒转录因子，在视网膜发生中具有此前未被怀疑的作用。我们发现Eomes在发育中的RGC中表达，并且是Pou4f2功能的介导者。Pou4f2通过保守视网膜增强子内的顺式调控元件直接调节Eomes的表达。在发育中的视网膜中删除Eomes会导致类似于Pou4f2基因敲除视网膜中的缺陷。此外，Eomes基因敲除胚胎视神经中的髓鞘形成严重受损，这表明Eomes调节这一过程。我们得出结论，Eomes是位于Pou4f2下游紧邻位置的关键调节因子，是RGC分化和视神经发育所必需的。
