In the vertebrate eye, Notch ligands, receptors, and ternary complex components determine the destiny of retinal progenitor cells in part by regulating Hes effector gene activity. There are multiple paralogues for nearly every node in this pathway, which results in numerous instances of redundancy and compensation during development. To dissect such complexity at the earliest stages of eye development, we used seven germline or conditional mutant mice and two spatiotemporally distinct Cre drivers. We perturbed the Notch ternary complex and multiple Hes genes to understand if Notch regulates optic stalk/nerve head development; and to test intracellular pathway components for their Notch-dependent versus -independent roles during retinal ganglion cell and cone photoreceptor competence and fate acquisition. We confirmed that disrupting Notch signaling universally blocks progenitor cell growth, but delineated specific pathway components that can act independently, such as sustained Hes1 expression in the optic stalk/nerve head. In retinal progenitor cells, we found that among the genes tested, they do not uniformly suppress retinal ganglion cell or cone differentiation; which is not due differences in developmental timing. We discovered that shifts in the earliest cell fates correlate with expression changes for the early photoreceptor factor Otx2, but not with Atoh7, a factor required for retinal ganglion cell formation. During photoreceptor genesis we also better defined multiple and simultaneous activities for Rbpj and Hes1 and identify redundant activities that occur downstream of Notch. Given its unique roles at the retina-optic stalk boundary and cone photoreceptor genesis, our data suggest Hes1 as a hub where Notch-dependent and -independent inputs converge.

中文翻译：

---

Notch 通路突变体不会同等地扰乱小鼠胚胎视网膜发育。

在脊椎动物的眼睛中，Notch配体、受体和三元复合体成分部分通过调节Hes效应基因活性来决定视网膜祖细胞的命运。该通路中几乎每个节点都有多个旁系同源物，这导致开发过程中出现大量冗余和补偿实例。为了剖析眼睛发育最早阶段的这种复杂性，我们使用了七只种系或条件突变小鼠和两个时空不同的 Cre 驱动程序。我们扰乱了Notch三元复合物和多个Hes基因，以了解Notch是否调节视柄/神经头发育；并测试细胞内通路成分在视网膜神经节细胞和视锥细胞的能力和命运获取过程中的Notch依赖性与非依赖性作用。我们证实，破坏Notch信号传导普遍会阻碍祖细胞生长，但描绘了可以独立发挥作用的特定途径成分，例如视柄/神经头中的持续Hes1表达。在视网膜祖细胞中，我们发现在测试的基因中，它们并没有一致地抑制视网膜神经节细胞或视锥细胞分化；这不是由于发育时间的差异造成的。我们发现，最早细胞命运的变化与早期感光因子 Otx2 的表达变化相关，但与 Atoh7（视网膜神经节细胞形成所需的因子）无关。在光感受器发生过程中，我们还更好地定义了 Rbpj 和 Hes1 的多个同时活动，并确定了 Notch 下游发生的冗余活动。鉴于其在视网膜视柄边界和视锥光感受器发生中的独特作用，我们的数据表明Hes1是Notch依赖和独立输入汇聚的枢纽。