The Ath5 proneural genes function upstream of Brn3 POU domain transcription factor genes to promote retinal ganglion cell development
The Ath5 proneural genes function upstream of Brn3 POU domain transcription factor genes to promote retinal ganglion cell development
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DOI：
10.1073/pnas.98.4.1649
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发表时间：
2001-02-13
影响因子：
11.1
通讯作者：
Xiang, MQ
中科院分区：
文献类型：
--
作者：
Liu, W;Mo, ZQ;Xiang, MQ
在视网膜发生过程中，非洲爪蟾碱性螺旋-环-螺旋转录因子Xath 5已被证明促进神经节细胞的命运。在发育中的小鼠和鸡视网膜中，基因靶向和过表达研究已经证明Brn 3 POU结构域转录因子基因在促进神经节细胞分化中的关键作用。然而，Ath 5和Brn 3基因之间的遗传关系尚不清楚。为了了解控制视网膜神经节细胞发育的遗传调控网络，我们通过在鸡胚胎中使用功能获得方法分析了Ath 5和Brn 3基因之间的关系。我们发现，在视网膜发生过程中，鸡Ath 5基因（Cath 5）在视网膜祖细胞和分化的神经节细胞中表达，但在终末分化的神经节细胞中不存在。Cath 5和小鼠Ath 5基因（Math 5）在视网膜祖细胞中的强制表达激活了cBrn 3c的表达，遵循中心到外周和颞到鼻的梯度。因此，与Xath 5蛋白类似，Cath 5和Math 5蛋白都具有促进神经节细胞发育的能力。此外，我们发现所有三个Brn 3基因的强制表达也可以刺激cBrn 3c的表达。我们进一步发现，Ath 5和Brn 3蛋白能够反式激活Brn 3b启动子。因此，这些数据表明，鸡中的cBrn 3c和小鼠中的Brn 3b的表达最初由新产生的神经节细胞中的Ath 5因子激活，随后由分化的神经节细胞中的Brn 3因子的反馈环维持。
During retinogenesis, the Xenopus basic helix-loop-helix transcription factor Xath5 has been shown to promote a ganglion cell fate. In the developing mouse and chicken retinas, gene targeting and overexpression studies have demonstrated critical roles for the Brn3 POU domain transcription factor genes in the promotion of ganglion cell differentiation. However, the genetic relationship between Ath5 and Brn3 genes is unknown. To understand the genetic regulatory network(s) that controls retinal ganglion cell development, we analyzed the relationship between Ath5 and Brn3 genes by using a gain-of-function approach in the chicken embryo. We found that during retinogenesis, the chicken Ath5 gene (Cath5) is expressed in retinal progenitors and in differentiating ganglion cells but is absent in terminally differentiated ganglion cells. Forced expression of both Cath5 and the mouse Ath5 gene (Math5) in retinal progenitors activates the expression of cBrn3c following central-to-peripheral and temporal-to-nasal gradients. As a result, similar to the Xath5 protein, both Cath5 and Math5 proteins have the ability to promote the development of ganglion cells. Moreover, we found that forced expression of all three Brn3 genes also can stimulate the expression of cBrn3c. We further found that Ath5 and Brn3 proteins are capable of transactivating a Brn3b promoter. Thus, these data suggest that the expression of cBrn3c in the chicken and Brn3b in the mouse is initially activated by Ath5 factors in newly generated ganglion cells and later maintained by a feedback loop of Brn3 factors in the differentiated ganglion cells.