Kugler Martina, Schlecht Anja, Fuchshofer Rudolf, Schmitt Sabrina I, Kleiter Ingo, Aigner Ludwig, Tamm Ernst R, Braunger Barbara M
Institute of Human Anatomy and Embryology, University of Regensburg, Regensburg, Germany.
Department of Neurology, St. Josef-Hospital, Bochum, Germany.
Histochem Cell Biol. 2017 Jul;148(1):21-32. doi: 10.1007/s00418-017-1549-5. Epub 2017 Mar 3.
The transforming growth factor-β (TGF-β) pathway contributes to maintain the quiescence of adult neural stem and progenitor cells in the brain. In the retina, Müller cells are discussed to represent a glial cell population with progenitor-like characteristics. Here, we aimed to investigate if elevated TGF-β signaling modulates the proliferation of Müller cells during retinal development. We generated mutant mice with a systemic, heterozygous up-regulation of TGF-β signaling by deleting its inhibitor SMAD7. We investigated apoptosis, proliferation, and differentiation of Müller cells in the developing retina. We show that a heterozygous deletion of SMAD7 results in an increased proliferation of Müller cell progenitors in the central retina at postnatal day 4, the time window when Müller cells differentiate in the mouse retina. This in turn results in a thickened retina and inner nuclear layer and a higher number of differentiated Müller cells in the more developed retina. Müller cells in mutant mice contain higher amounts of nestin than those of control animals which indicates that the increase in TGF-β signaling activity during retinal development contribute to maintain some progenitor-like characteristics in Müller cells even after their differentiation period. We conclude that TGF-β signaling influences Müller cell proliferation and differentiation during retinal development.
转化生长因子-β（TGF-β）信号通路有助于维持成年大脑中神经干细胞和祖细胞的静止状态。在视网膜中，有人认为穆勒细胞代表具有祖细胞样特征的神经胶质细胞群体。在此，我们旨在研究TGF-β信号增强是否会在视网膜发育过程中调节穆勒细胞的增殖。我们通过删除其抑制剂SMAD7，构建了TGF-β信号全身性杂合上调的突变小鼠。我们研究了发育中视网膜中穆勒细胞的凋亡、增殖和分化情况。我们发现，杂合缺失SMAD7会导致出生后第4天（即小鼠视网膜中穆勒细胞分化的时间窗）中央视网膜中穆勒细胞祖细胞的增殖增加。这进而导致视网膜和内核层增厚，以及在发育更成熟的视网膜中有更多已分化的穆勒细胞。与对照动物相比，突变小鼠中的穆勒细胞含有更多的巢蛋白，这表明视网膜发育过程中TGF-β信号活性的增加有助于穆勒细胞即使在分化期后仍保持一些祖细胞样特征。我们得出结论，TGF-β信号在视网膜发育过程中影响穆勒细胞的增殖和分化。
