Regulation of Brn3b by DLX1 and DLX2 is required for retinal ganglion cell differentiation in the vertebrate retina.
Regulation of Brn3b by DLX1 and DLX2 is required for retinal ganglion cell differentiation in the vertebrate retina.
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DOI：
10.1242/dev.142042
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发表时间：
2017-05-01
期刊：
影响因子：
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通讯作者：
Eisenstat DD
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作者：
Zhang Q;Zagozewski J;Cheng S;Dixit R;Zhang S;de Melo J;Mu X;Klein WH;Brown NL;Wigle JT;Schuurmans C;Eisenstat DD
调节视网膜神经节细胞（RGC）的分化和轴突导向是功能性视觉系统所必需的。同源结构域和碱性螺旋-环-螺旋转录因子是视网膜发生以及特定视网膜细胞类型的形成、分化和维持所必需的。我们假设Dlx 1，Dlx 2和Brn 3b同源框基因在平行的内在途径中起作用，以确定RGC的命运，因此产生了Dlx 1/Dlx 2/Brn 3b三重敲除小鼠。在Dlx 1/Dlx 2/Brn 3b缺失视网膜中发现了比通过结合Brn 3b单敲除视网膜和Dlx 1/Dlx 2双敲除视网膜的特征所预测的更严重的视网膜表型，包括几乎完全的RGC损失以及神经节细胞层中无长突细胞的显著增加。此外，我们发现DLX 1和DLX 2作为Brn 3b表达的直接转录激活因子起作用。原代胚胎视网膜培养物中Dlx 2表达的敲低和Dlx 2在子宫内功能的获得强烈支持DLX 2对于Brn 3b在体内的表达是必要的和足够的。我们认为，ATOH 7指定RGC-承诺的祖细胞和Dlx 1和Dlx 2功能下游的ATOH 7和平行，但合作，涉及调节Brn 3b表达的途径，以确定RGC的命运。总结：Dlx 1/2同源框基因通过直接激活Brn 3b表达来调节视网膜神经节细胞（RGC）分化;因此，Dlx 1/Dlx 2/Brn 3b三重敲除小鼠表现出几乎完全的RGC丧失。
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 Dlx1, Dlx2 and Brn3b homeobox genes function in parallel intrinsic pathways to determine RGC fate and therefore generated Dlx1/Dlx2/Brn3b triple-knockout mice. A more severe retinal phenotype was found in the Dlx1/Dlx2/Brn3b-null retinas than was predicted by combining features of the Brn3b single- and Dlx1/Dlx2 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 Brn3b expression. Knockdown of Dlx2 expression in primary embryonic retinal cultures and Dlx2 gain of function in utero strongly support that DLX2 is both necessary and sufficient for Brn3b expression in vivo. We suggest that ATOH7 specifies RGC-committed progenitors and that Dlx1 and Dlx2 function both downstream of ATOH7 and in parallel, but cooperative, pathways that involve regulation of Brn3b expression to determine RGC fate. Summary: Dlx1/2 homeobox genes regulate retinal ganglion cell (RGC) differentiation by directly activating Brn3b expression; accordingly, Dlx1/Dlx2/Brn3b triple-knockout mice exhibit near complete RGC loss.