Riesenberg Amy N, Liu Zhenyi, Kopan Raphael, Brown Nadean L
Division of Developmental Biology, Cincinnati Children's Research Foundation, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.
J Neurosci. 2009 Oct 14;29(41):12865-77. doi: 10.1523/JNEUROSCI.3382-09.2009.
Vertebrate retinal progenitor cells (RPCs) are pluripotent, but pass through competence states that progressively restrict their developmental potential (Cepko et al., 1996; Livesey and Cepko, 2001; Cayouette et al., 2006). In the rodent eye, seven retinal cell classes differentiate in overlapping waves, with RGCs, cone photoreceptors, horizontals, and amacrines forming predominantly before birth, and rod photoreceptors, bipolars, and Müller glia differentiating postnatally. Both intrinsic and extrinsic factors regulate each retinal cell type (for review, see Livesey and Cepko, 2001). Here, we conditionally deleted the transcription factor Rbpj, a critical integrator of multiple Notch signals (Jarriault et al., 1995; Honjo, 1996; Kato et al., 1997; Han et al., 2002), during prenatal mouse retinal neurogenesis. Removal of Rbpj caused reduced proliferation, premature neuronal differentiation, apoptosis, and profound mispatterning. To determine the cell autonomous requirements for Rbpj during RGC and cone formation, we marked Cre-generated retinal lineages with GFP expression, which showed that Rbpj autonomously promotes RPC mitotic activity, and suppresses RGC and cone fates. In addition, the progressive loss of Rbpj-/- RPCs resulted in a diminished progenitor pool available for rod photoreceptor formation. This circumstance, along with the overproduction of Rbpj-/- cones, revealed that photoreceptor development is under homeostatic regulation. Finally, to understand how the Notch pathway regulates the simultaneous formation of multiple cell types, we compared the RGC and cone phenotypes of Rbpj to Notch1 (Jadhav et al., 2006b; Yaron et al., 2006), Notch3, and Hes1 mutants. We found particular combinations of Notch pathway genes regulate the development of each retinal cell type.
脊椎动物视网膜祖细胞（RPCs）具有多能性，但会经历一些能力状态，这些状态会逐渐限制它们的发育潜能（塞普科等人，1996年；利夫西和塞普科，2001年；卡尤埃特等人，2006年）。在啮齿动物眼中，七种视网膜细胞类型以重叠的波峰形式分化，视网膜神经节细胞（RGCs）、视锥光感受器、水平细胞和无长突细胞主要在出生前形成，而视杆光感受器、双极细胞和穆勒胶质细胞在出生后分化。内在和外在因素都调节每种视网膜细胞类型（综述见利夫西和塞普科，2001年）。在此，我们在小鼠产前视网膜神经发生过程中条件性地删除了转录因子Rbpj，它是多种Notch信号的关键整合因子（雅里奥等人，1995年；本庶佑，1996年；加藤等人，1997年；韩等人，2002年）。去除Rbpj导致增殖减少、神经元过早分化、细胞凋亡以及严重的模式紊乱。为了确定在RGC和视锥形成过程中Rbpj对细胞自主性的需求，我们用绿色荧光蛋白（GFP）表达标记由Cre产生的视网膜谱系，结果表明Rbpj自主促进RPC的有丝分裂活性，并抑制RGC和视锥细胞的命运。此外，Rbpj-/- RPCs的逐渐减少导致可用于视杆光感受器形成的祖细胞池减少。这种情况，再加上Rbpj-/-视锥细胞的过度产生，表明光感受器的发育受到稳态调节。最后，为了了解Notch信号通路如何调节多种细胞类型的同时形成，我们将Rbpj的RGC和视锥细胞表型与Notch1（贾德哈夫等人，2006b；亚龙等人，2006）、Notch3和Hes1突变体进行了比较。我们发现Notch信号通路基因的特定组合调节每种视网膜细胞类型的发育。
