Forkhead box N4 (Foxn4) activates Dll4-Notch signaling to suppress photoreceptor cell fates of early retinal progenitors
Forkhead box N4 (Foxn4) activates Dll4-Notch signaling to suppress photoreceptor cell fates of early retinal progenitors
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DOI：
10.1073/pnas.1115767109
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发表时间：
2012-02-28
影响因子：
11.1
通讯作者：
Xiang, Mengqing
中科院分区：
文献类型：
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作者：
Luo, Huijun;Jin, Kangxin;Xiang, Mengqing
在发育过程中从多能祖细胞产生不同的神经元类型和亚型对于在成人中枢神经系统中组装功能性神经回路至关重要。在小鼠视网膜发生过程中，早期视网膜祖细胞产生几种细胞类型，包括神经节细胞、无长突细胞、水平细胞、视锥细胞和视杆细胞。目前尚不清楚这些命运中的每一个是如何从早期祖细胞可用的多种神经元命运中选择的。通过使用生物信息学、遗传学和生物化学方法的组合，我们研究了Foxn 4从多能视网膜祖细胞中选择无长突细胞和水平细胞命运的机制。这些研究表明，Foxn 4具有通过选择性激活Dll 4-Notch信号传导来抑制早期视网膜祖细胞的替代感光细胞命运的内在活性。基因表达和条件性消融分析揭示，Dll 4直接被Foxn 4通过转录遗传学上保守的增强子激活，并且Dll 4可以通过充当主要Notch配体来部分介导Foxn 4功能，以扩大祖细胞库并限制光感受器产生。我们的数据共同定义了Foxn 4介导的分子和信号通路，该通路是抑制早期视网膜祖细胞的替代细胞命运的基础。
The generation of diverse neuronal types and subtypes from multipotent progenitors during development is crucial for assembling functional neural circuits in the adult central nervous system. During mouse retinogenesis, early retinal progenitors give rise to several cell types, including ganglion, amacrine, horizontal, cone, and rod cells. It is unknown at present how each of these fates is selected from the multiple neuronal fates available to the early progenitor. By using a combination of bioinformatic, genetic, and biochemical approaches, we investigated the mechanism by which Foxn4 selects the amacrine and horizontal cell fates from multipotential retinal progenitors. These studies indicate that Foxn4 has an intrinsic activity to suppress the alternative photoreceptor cell fates of early retinal progenitors by selectively activating Dll4-Notch signaling. Gene expression and conditional ablation analyses reveal that Dll4 is directly activated by Foxn4 via phylogenetically conserved enhancers and that Dll4 can partly mediate the Foxn4 function by serving as a major Notch ligand to expand the progenitor pool and limit photoreceptor production. Our data together define a Foxn4-mediated molecular and signaling pathway that underlies the suppression of alternative cell fates of early retinal progenitors.