Retinal neurons regulate proliferation of postnatal progenitors and Muller glia in the rat retina via TGFβ signaling
Retinal neurons regulate proliferation of postnatal progenitors and Muller glia in the rat retina via TGFβ signaling
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DOI：
10.1242/dev.01882
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发表时间：
2005-07-01
期刊：
影响因子：
4.6
通讯作者：
Reh, TA
中科院分区：
文献类型：
--
作者：
Close, JL;Gumuscu, B;Reh, TA
啮齿动物视网膜中增殖细胞的数量在出生后急剧下降。为了确定视网膜微环境中的外在因素是否导致增殖下降，我们建立了视网膜祖细胞或米勒胶质细胞的培养物，并添加了来自较老视网膜的分离的视网膜神经元。老细胞抑制祖细胞和米勒神经胶质细胞的增殖。当这些实验在 TGF β RII-Fc 融合蛋白（一种 TGF β 信号传导抑制剂）存在的情况下进行时，增殖得以恢复。这表明视网膜衍生的 TGF β 信号是视网膜增殖发育下降的原因。 TGF β 受体 I 和 II 在视网膜中表达，位于发育早期的巢蛋白阳性祖细胞和发育后期的 Glast 阳性 Muller 胶质细胞中。 RT-PCR和免疫荧光数据显示TGFβ2是出生后视网膜中表达最高的TGFβ配体，并且由视网膜内神经元表达。在出生后第4天的视网膜中添加TGFβ1或TGFβ2可显着抑制祖细胞增殖，而用TGFβ信号抑制剂处理移植的出生后第6天的视网膜会导致增殖增加。最后，我们通过注射TGFβ信号抑制剂来测试TGFβ在体内的作用：当出生后第5.5天抑制TGFβ信号时，中央视网膜的增殖增加；当出生后第 10 天与 EGF 共同注射时，TGF β 抑制剂会刺激 Muller 胶质细胞增殖。总之，这些结果表明，视网膜神经元产生细胞抑制性 TGF β 信号，维持出生后大鼠视网膜有丝分裂的静止状态。
The number of proliferating cells in the rodent retina declines dramatically after birth. To determine if extrinsic factors in the retinal micro-environment are responsible for this decline in proliferation, we established cultures of retinal progenitors or Muller glia, and added dissociated retinal neurons from older retinas. The older cells inhibited proliferation of progenitor cells and Muller glia. When these experiments were performed in the presence of TGF beta RII-Fc fusion protein, an inhibitor of TGF beta signaling, proliferation was restored. This suggests a retina-derived TGF beta signal is responsible for the developmental decline in retinal proliferation. TGF beta receptors I and II are expressed in the retina and are located in nestin-positive progenitors early in development and glast-positive Muller glia later in development. RT-PCR and immunofluorescence data show TGF beta 2 is the most highly expressed TGF beta ligand in the postnatal retina, and it is expressed by inner retinal neurons. Addition of either TGF beta 1 or TGF beta 2 to postnatal day 4 retinas significantly inhibited progenitor proliferation, while treatment of explanted postnatal day 6 retinas with TGF beta signaling inhibitors resulted in increased proliferation. Last, we tested the effects of TGF beta in vivo by injections of TGF beta signaling inhibitors: when TGF beta signaling is inhibited at postnatal day 5.5, proliferation is increased in the central retina; and when co-injected with EGF at postnatal day 10, TGF beta inhibitors stimulate Muller glial proliferation. In sum, these results show that retinal neurons produce a cytostatic TGF beta signal that maintains mitotic quiescence in the postnatal rat retina.