Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, United States.
Division of Experimental Retinal Therapies, Department of Clinical Sciences and Advanced Medicine, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, United States.
Sci Rep. 2018 Aug 22;8(1):12544. doi: 10.1038/s41598-018-30492-9.
Ndr2/Stk38l encodes a protein kinase associated with the Hippo tumor suppressor pathway and is mutated in a naturally-occurring canine early retinal degeneration (erd). To elucidate the retinal functions of Ndr2 and its paralog Ndr1/Stk38, we generated Ndr1 and Ndr2 single knockout mice. Although retinal lamination appeared normal in these mice, Ndr deletion caused a subset of Pax6-positive amacrine cells to proliferate in differentiated retinas, while concurrently decreasing the number of GABAergic, HuD and Pax6-positive amacrine cells. Retinal transcriptome analyses revealed that Ndr2 deletion increased expression of neuronal stress genes and decreased expression of synaptic organization genes. Consistent with the latter, Ndr deletion dramatically reduced levels of Aak1, an Ndr substrate that regulates vesicle trafficking. Our findings indicate that Ndr kinases are important regulators of amacrine and photoreceptor cells and suggest that Ndr kinases inhibit the proliferation of a subset of terminally differentiated cells and modulate interneuron synapse function via Aak1.
Ndr2/Stk38l 编码一种与 Hippo 肿瘤抑制途径相关的蛋白激酶，并且在一种自然发生的犬早期视网膜变性（erd）中发生突变。为了阐明 Ndr2 及其同源物 Ndr1/Stk38 的视网膜功能，我们生成了 Ndr1 和 Ndr2 单敲除小鼠。尽管这些小鼠的视网膜分层看起来正常，但 Ndr 缺失导致一部分 Pax6 阳性无长突细胞在分化的视网膜中增殖，同时减少 GABA 能、HuD 和 Pax6 阳性无长突细胞的数量。视网膜转录组分析显示，Ndr2 缺失增加了神经元应激基因的表达，降低了突触组织基因的表达。与后者一致，Ndr 缺失显著降低了 Aak1 的水平，Aak1 是一种调节囊泡运输的 Ndr 底物。我们的研究结果表明，Ndr 激酶是无长突细胞和光感受器细胞的重要调节因子，并表明 Ndr 激酶通过 Aak1 抑制一组终末分化细胞的增殖，并调节中间神经元突触功能。
