Fujitani Yoshio, Fujitani Shuko, Luo Huijun, Qiu Feng, Burlison Jared, Long Qiaoming, Kawaguchi Yoshiya, Edlund Helena, MacDonald Raymond J, Furukawa Takahisa, Fujikado Takashi, Magnuson Mark A, Xiang Mengqing, Wright Christopher V E
Vanderbilt University Program in Developmental Biology and Department of Cell and Developmental Biology, Vanderbilt University Medical School, Nashville, TN 37232-8240, USA.
Development. 2006 Nov;133(22):4439-50. doi: 10.1242/dev.02598.
The vertebrate neural retina comprises six classes of neurons and one class of glial cells, all derived from a population of multipotent progenitors. There is little information on the molecular mechanisms governing the specification of cell type identity from multipotent progenitors in the developing retina. We report that Ptf1a, a basic-helix-loop-helix (bHLH) transcription factor, is transiently expressed by post-mitotic precursors in the developing mouse retina. Recombination-based lineage tracing analysis in vivo revealed that Ptf1a expression marks retinal precursors with competence to exclusively produce horizontal and amacrine neurons. Inactivation of Ptf1a leads to a fate-switch in these precursors that causes them to adopt a ganglion cell fate. This mis-specification of neurons results in a complete loss of horizontal cells, a profound decrease of amacrine cells and an increase in ganglion cells. Furthermore, we identify Ptf1a as a primary downstream target for Foxn4, a forkhead transcription factor involved in the genesis of horizontal and amacrine neurons. These data, together with the previous findings on Foxn4, provide a model in which the Foxn4-Ptf1a pathway plays a central role in directing the differentiation of retinal progenitors towards horizontal and amacrine cell fates.
脊椎动物的神经视网膜由六类神经元和一类神经胶质细胞组成，所有这些细胞均源自一群多能祖细胞。关于发育中的视网膜中多能祖细胞如何决定细胞类型身份的分子机制，目前所知甚少。我们报告称，Ptf1a是一种碱性螺旋-环-螺旋（bHLH）转录因子，在发育中的小鼠视网膜有丝分裂后的前体细胞中短暂表达。体内基于重组的谱系追踪分析表明，Ptf1a的表达标记了视网膜前体细胞，这些前体细胞有能力专门产生水平细胞和无长突细胞。Ptf1a的失活导致这些前体细胞命运转变，使其转而采用神经节细胞命运。神经元的这种错误指定导致水平细胞完全缺失，无长突细胞大幅减少，神经节细胞增加。此外，我们确定Ptf1a是Foxn4的主要下游靶点，Foxn4是一种参与水平细胞和无长突细胞生成的叉头转录因子。这些数据，连同之前关于Foxn4的研究结果，提供了一个模型，其中Foxn4-Ptf1a通路在指导视网膜祖细胞向水平细胞和无长突细胞命运分化中起核心作用。
