Luft Veronika, Reinhard Jacqueline, Shibuya Masabumi, Fischer Klaus D, Faissner Andreas
Department of Cell Morphology & Molecular Neurobiology, Ruhr-University Bochum, NDEF 05/594 Universitaetsstrasse 150, 44780, Bochum, Germany.
International Graduate School of Neuroscience (IGSN), FNO 1/116 Universitaetsstrasse 150, 44780, Bochum, Germany.
Cell Tissue Res. 2015 Feb;359(2):423-440. doi: 10.1007/s00441-014-2050-2. Epub 2014 Dec 12.
The seven main cell types in the mammalian retina arise from multipotent retinal progenitor cells, a process that is tightly regulated by intrinsic and extrinsic signals. However, the molecular mechanisms that control proliferation, differentiation and cell-fate decisions of retinal progenitor cells are not fully understood yet. Here, we report that the guanine nucleotide exchange factor Vav3, a regulator of Rho-GTPases, is involved in retinal development. We demonstrate that Vav3 is expressed in the mouse retina during the embryonic period. In order to study the role of Vav3 in the developing retina, we generate Vav3-deficient mice. The loss of Vav3 results in an accelerated differentiation of retinal ganglion cells and cone photoreceptors during early and late embryonic development. We provide evidence that more retinal progenitor cells express the late progenitor marker Sox9 in Vav3-deficient mice than in wild-types. This premature differentiation is compensated during the postnatal period and late-born cell types such as bipolar cells and Müller glia display normal numbers. Taken together, our data imply that Vav3 is a regulator of retinal progenitor cell differentiation, thus highlighting a novel role for guanine nucleotide exchange factors in retinogenesis.
哺乳动物视网膜中的七种主要细胞类型源自多能视网膜祖细胞，这一过程受到内在和外在信号的严格调控。然而，控制视网膜祖细胞增殖、分化和细胞命运决定的分子机制尚未完全明了。在此，我们报告鸟嘌呤核苷酸交换因子Vav3（一种Rho - GTPases调节剂）参与视网膜发育。我们证明Vav3在胚胎期小鼠视网膜中表达。为了研究Vav3在发育中视网膜的作用，我们构建了Vav3基因缺失小鼠。Vav3的缺失导致胚胎早期和晚期视网膜神经节细胞和视锥光感受器的分化加速。我们提供的证据表明，与野生型小鼠相比，Vav3基因缺失小鼠中有更多的视网膜祖细胞表达晚期祖细胞标志物Sox9。这种过早分化在出生后阶段得到补偿，出生较晚的细胞类型如双极细胞和穆勒胶质细胞数量正常。综上所述，我们的数据表明Vav3是视网膜祖细胞分化的调节剂，从而凸显了鸟嘌呤核苷酸交换因子在视网膜发生中的新作用。
