Zhang Qi, Zagozewski Jamie, Cheng Shaohong, Dixit Rajiv, Zhang Shunzhen, de Melo Jimmy, Mu Xiuqian, Klein William H, Brown Nadean L, Wigle Jeffrey T, Schuurmans Carol, Eisenstat David D
Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, Canada R3E 0J9.
Department of Medical Genetics, University of Alberta, Edmonton, Canada T6G 2H7.
Development. 2017 May 1;144(9):1698-1711. doi: 10.1242/dev.142042. Epub 2017 Mar 29.
Regulated retinal ganglion cell (RGC) differentiation and axonal guidance is required for a functional visual system. Homeodomain and basic helix-loop-helix transcription factors are required for retinogenesis, as well as patterning, differentiation and maintenance of specific retinal cell types. We hypothesized that , and homeobox genes function in parallel intrinsic pathways to determine RGC fate and therefore generated // triple-knockout mice. A more severe retinal phenotype was found in the //-null retinas than was predicted by combining features of the single- and / double-knockout retinas, including near total RGC loss with a marked increase in amacrine cells in the ganglion cell layer. Furthermore, we discovered that DLX1 and DLX2 function as direct transcriptional activators of expression. Knockdown of expression in primary embryonic retinal cultures and gain of function strongly support that DLX2 is both necessary and sufficient for expression We suggest that ATOH7 specifies RGC-committed progenitors and that and function both downstream of ATOH7 and in parallel, but cooperative, pathways that involve regulation of expression to determine RGC fate.
功能性视觉系统需要视网膜神经节细胞（RGC）的分化和轴突导向受到调控。同源结构域和碱性螺旋-环-螺旋转录因子对于视网膜发生以及特定视网膜细胞类型的模式形成、分化和维持是必需的。我们推测， 、 和 同源框基因在平行的内在途径中发挥作用以决定RGC命运，因此构建了 // 三敲除小鼠。在 // 基因敲除的视网膜中发现了比通过 单敲除和 / 双敲除视网膜特征组合所预测的更为严重的视网膜表型，包括神经节细胞层中几乎完全的RGC丢失以及无长突细胞显著增加。此外，我们发现DLX1和DLX2作为 表达的直接转录激活因子发挥作用。在原代胚胎视网膜培养物中敲低 表达以及 功能获得性研究有力支持DLX2对于 表达既是必需的也是充分的。我们认为ATOH7指定了RGC定向祖细胞，并且 和 在ATOH7下游以及平行但协同的途径中发挥作用，这些途径涉及对 表达的调控以决定RGC命运。
