Department of Ophthalmology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Neuroscience Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Department of Ophthalmology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Dev Biol. 2020 Aug 15;464(2):111-123. doi: 10.1016/j.ydbio.2020.06.003. Epub 2020 Jun 17.
The transcription factors Prdm1 (Blimp1) and Vsx2 (Chx10) work downstream of Otx2 to regulate photoreceptor and bipolar cell fates in the developing retina. Mice that lack Vsx2 fail to form bipolar cells while Prdm1 mutants form excess bipolars at the direct expense of photoreceptors. Excess bipolars in Prdm1 mutants appear to derive from rods, suggesting that photoreceptor fate remains mutable for some time after cells become specified. Here we tested whether bipolar cell fate is also plastic during development. To do this, we created a system to conditionally misexpress Prdm1 at different stages of bipolar cell development. We found that Prdm1 blocks bipolar cell formation if expressed before the fate choice decision occurred. When we misexpressed Prdm1 just after the decision to become a bipolar cell was made, some cells were reprogrammed into photoreceptors. In contrast, Prdm1 misexpression in mature bipolar cells did not affect cell fate. We also provide evidence that sustained misexpression of Prdm1 was selectively toxic to photoreceptors. Our data show that bipolar fate is malleable, but only for a short temporal window following fate specification. Prdm1 and Vsx2 act by stabilizing photoreceptor and bipolar fates in developing OTX2+ cells of the retina.
转录因子 Prdm1（Blimp1）和 Vsx2（Chx10）在 Otx2 下游发挥作用，调节发育中的视网膜中的光感受器和双极细胞命运。缺乏 Vsx2 的小鼠未能形成双极细胞，而 Prdm1 突变体则以牺牲光感受器为代价形成过多的双极细胞。Prdm1 突变体中的多余双极细胞似乎来自视杆细胞，这表明在细胞被指定后，光感受器命运在一段时间内仍然是可塑的。在这里，我们测试了双极细胞命运在发育过程中是否也是可塑的。为此，我们创建了一个系统，在双极细胞发育的不同阶段条件性地过表达 Prdm1。我们发现，如果在命运选择决定发生之前表达 Prdm1，则 Prdm1 会阻止双极细胞的形成。当我们在决定成为双极细胞后立即过表达 Prdm1 时，一些细胞被重新编程为光感受器。相比之下，在成熟的双极细胞中过表达 Prdm1 不会影响细胞命运。我们还提供了证据表明，Prdm1 的持续过表达对光感受器具有选择性毒性。我们的数据表明，双极命运是可塑的，但仅在命运指定后很短的时间窗口内。Prdm1 和 Vsx2 通过在视网膜的 OTX2+细胞中稳定光感受器和双极细胞命运来发挥作用。
