Klimova Lucie, Antosova Barbora, Kuzelova Andrea, Strnad Hynek, Kozmik Zbynek
Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Videnska 1083, 14420 Prague 4, Czech Republic.
Dev Biol. 2015 Jun 1;402(1):48-60. doi: 10.1016/j.ydbio.2015.02.023. Epub 2015 Mar 18.
Genetic studies of the last decades strongly indicated that generation of particular retinal cell types is governed by gene regulatory networks of transcription factors and their target genes. The paired and homeodomain transcription factor Pax6 plays a pivotal role in retinal development as its inactivation in the retinal progenitor cell population leads to abolished differentiation of all retinal cell types. However, until now, only a few transcription factors operating downstream of Pax6 responsible for generation of individual retinal cell types have been identified. In this study, we identified two transcription factors of the Onecut family, Onecut1 and Onecut2, as Pax6 downstream-acting factors. Onecut1 and Onecut2 were previously shown to be expressed in developing horizontal cells, retinal ganglion cells and cone photoreceptors; however, their role in differentiation of these cell types is poorly understood. In this study, we show that the horizontal cell genesis is severely disturbed in Onecut-deficient retinae. In single Onecut1 and Onecut2 mutants, the number of horizontal cells is dramatically reduced while horizontal cells are completely missing in the Onecut1/Onecut2 compound mutant. Analysis of genes involved in the horizontal cell genesis such as Foxn4, Ptf1a, Prox1 and Lim1 showed that although horizontal cells are initially formed, they are not maintained in Onecut-deficient retinae. Taken together, this study suggests the model in which Pax6 regulates the maintenance of horizontal cells through the activation of Onecut1 and Onecut2 transcription factors.
过去几十年的遗传学研究有力地表明，特定视网膜细胞类型的产生受转录因子及其靶基因的基因调控网络支配。配对且含有同源结构域的转录因子Pax6在视网膜发育中起关键作用，因为其在视网膜祖细胞群体中的失活会导致所有视网膜细胞类型的分化被阻断。然而，到目前为止，仅鉴定出少数几个在Pax6下游发挥作用、负责特定视网膜细胞类型产生的转录因子。在本研究中，我们鉴定出Onecut家族的两个转录因子Onecut1和Onecut2为Pax6的下游作用因子。此前已表明Onecut1和Onecut2在发育中的水平细胞、视网膜神经节细胞和视锥光感受器中表达；然而，它们在这些细胞类型分化中的作用却知之甚少。在本研究中，我们发现Onecut缺陷型视网膜中的水平细胞发生严重紊乱。在单个Onecut1和Onecut2突变体中，水平细胞数量显著减少，而在Onecut1/Onecut2复合突变体中水平细胞完全缺失。对参与水平细胞发生的基因（如Foxn4、Ptf1a、Prox1和Lim1）的分析表明，尽管水平细胞最初能够形成，但在Onecut缺陷型视网膜中它们无法维持。综上所述，本研究提出了一个模型，即Pax6通过激活Onecut1和Onecut2转录因子来调节水平细胞的维持。
