Lhx2 Is an Essential Factor for Retinal Gliogenesis and Notch Signaling
Lhx2 Is an Essential Factor for Retinal Gliogenesis and Notch Signaling
复制标题
DOI：
10.1523/jneurosci.3145-15.2016
复制
发表时间：
2016-02-24
影响因子：
5.3
通讯作者：
Blackshaw, Seth
中科院分区：
文献类型：
--
作者：
de Melo, Jimmy;Zibetti, Cristina;Blackshaw, Seth
穆勒胶质细胞(MG)是唯一一种由神经上皮祖细胞产生的神经胶质细胞类型，这些细胞产生脊椎动物视网膜。MG是维持视网膜动态平衡和支持视网膜神经元存活所必需的。此外，在某些脊椎动物类别中，MG作为成体干细胞发挥作用，介导损伤后的视网膜再生。然而，由于视网膜前体细胞和分化的MG之间的基因表达有相当大的重叠，因此调控MG发展的机制尚不清楚。我们发现LIM同源结构域转录因子LHX2在小鼠视网膜中是MG发生所必需的。时间控制的基因敲除研究表明，在MG发育的所有阶段都需要LHX2，从具有胶质能力的视网膜前体细胞的增殖，Muller特异性基因表达的激活，到MG形态特征的终末分化。我们发现LHX2通过直接调节Notch1、Dll1和Dll3等Notch通路基因以及Hes1、Hes5、Sox8和RAX等胶质形成转录因子的表达来调节胶质发生。条件性敲除LHX2导致Notch途径基因的快速下调和Notch信号的丢失。我们进一步证明，通过表达潜在的胶质形成Notch通路转录效应子Hes5而诱导的Muller胶质形成需要LHX2的表达。这些结果表明，LHX2不仅直接调节Notch信号通路组件的表达，而且与神经胶质形成的Notch通路一起驱动MG的规范和分化。
Muller glia (MG) are the only glial cell type produced by the neuroepithelial progenitor cells that generate the vertebrate retina. MG are required to maintain retinal homeostasis and support the survival of retinal neurons. Furthermore, in certain vertebrate classes, MG function as adult stem cells, mediating retinal regeneration in response to injury. However, the mechanisms that regulate MG development are poorly understood because there is considerable overlap in gene expression between retinal progenitor cells and differentiated MG. We show that the LIM homeodomain transcription factor Lhx2 is required for the development of MG in the mouse retina. Temporally controlled knock-out studies reveal a requirement for Lhx2 during all stages of MG development, ranging from the proliferation of gliocompetent retinal progenitors, activation of Muller-specific gene expression, and terminal differentiation of MG morphological features. We show that Lhx2 regulates gliogenesis in part by regulating directly the expression of Notch pathway genes including Notch1, Dll1, and Dll3 and gliogenic transcription factors such as Hes1, Hes5, Sox8, and Rax. Conditional knock-out of Lhx2 resulted in a rapid downregulation of Notch pathway genes and loss of Notch signaling. We further demonstrate that Muller gliogenesis induced by misex-pression of the potently gliogenic Notch pathway transcriptional effector Hes5 requires Lhx2 expression. These results indicate that Lhx2 not only directly regulates expression of Notch signaling pathway components, but also acts together with the gliogenic Notch pathway to drive MG specification and differentiation.