Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA; Graduate Program in Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
Cell Rep. 2019 May 7;27(6):1637-1649.e6. doi: 10.1016/j.celrep.2019.04.047.
In response to retinal damage, the Müller glial cells (MGs) of the zebrafish retina have the ability to undergo a cellular reprogramming event in which they enter the cell cycle and divide asymmetrically, thereby producing multipotent retinal progenitors capable of regenerating lost retinal neurons. However, mammalian MGs do not exhibit such a proliferative and regenerative ability. Here, we identify Hippo pathway-mediated repression of the transcription cofactor YAP as a core regulatory mechanism that normally blocks mammalian MG proliferation and cellular reprogramming. MG-specific deletion of Hippo pathway components Lats1 and Lats2, as well as transgenic expression of a Hippo non-responsive form of YAP (YAP5SA), resulted in dramatic Cyclin D1 upregulation, loss of adult MG identity, and attainment of a highly proliferative, progenitor-like cellular state. Our results reveal that mammalian MGs may have latent regenerative capacity that can be stimulated by repressing Hippo signaling.
针对视网膜损伤，斑马鱼视网膜中的 Müller 胶质细胞 (MGs) 具有经历细胞重编程事件的能力，即在该事件中它们进入细胞周期并不对称分裂，从而产生多能性视网膜祖细胞，能够再生丢失的视网膜神经元。然而，哺乳动物的 MGs 没有表现出这种增殖和再生能力。在这里，我们确定 Hippo 途径介导的转录共激活因子 YAP 的抑制是阻止哺乳动物 MG 增殖和细胞重编程的核心调节机制。MG 特异性敲除 Hippo 途径成分 Lats1 和 Lats2，以及转染表达 Hippo 无反应形式的 YAP (YAP5SA)，导致细胞周期蛋白 D1 的显著上调，成年 MG 特性的丧失，并获得高度增殖的祖细胞样细胞状态。我们的研究结果表明，哺乳动物的 MGs 可能具有潜在的再生能力，可以通过抑制 Hippo 信号来刺激。
