Department of Biochemistry and Molecular Biology, MD Anderson Cancer Center, University of Texas, Houston, Texas 77030, USA.
Invest Ophthalmol Vis Sci. 2011 May 2;52(6):2930-7. doi: 10.1167/iovs.10-5940.
The present study was aimed at defining developmental roles of Smad4, a key mediator of the TGF-β superfamily signaling system, in the embryonic mouse retina.
Using a Cre/loxP-mediated conditional gene targeting approach, Smad4 gene function was deleted from the embryonic mouse retina. Mutant phenotypes were morphologically and molecularly examined.
Loss of Smad4 in the developing retina led to varying degrees of microphthalmia at birth, presumably because of elevated apoptosis observed transiently at embryonic day 12.5 in the developing retina. This was also associated with an apparent delay in accumulation of retinal ganglion cells. Smad4 conditional mutants also exhibited alterations of retinal spatial patterning along the dorsal-ventral axis, consistent with a known function of BMP signaling in the embryonic retina. However, despite a known role for BMP signaling in retinal cell survival, proliferation, and differentiation, Smad4 mutant retinal progenitor cells were capable of maintaining growth and neurogenesis throughout embryonic development. We also found that the loss of Smad4 led to abnormal targeting of retinal ganglion cell axons to the optic nerve head, a phenotype consistent with reduced BMP signaling in the developing retina.
These results suggest that Smad4 is essential for a subset of, but not all, TGF-β/BMP-dependent developmental processes in the embryonic retina. In addition, genetic requirements for Smad4 in the embryonic retina are evident predominantly in the developmental events regulated by the BMP branch of the TGF-β signaling pathway.
本研究旨在确定 Smad4 在 TGF-β 超家族信号系统中的关键介质在胚胎小鼠视网膜中的发育作用。
使用 Cre/loxP 介导的条件性基因靶向方法，从胚胎小鼠视网膜中删除 Smad4 基因功能。对突变表型进行了形态和分子检查。
Smad4 在发育中的视网膜中的缺失导致出生时程度不同的小眼症，这可能是由于在胚胎 12.5 日观察到的发育中的视网膜中的细胞凋亡短暂升高所致。这也与视网膜神经节细胞的积累明显延迟有关。Smad4 条件性突变体还表现出沿背腹轴的视网膜空间模式的改变，这与 BMP 信号在胚胎视网膜中的已知功能一致。然而，尽管 BMP 信号在视网膜细胞存活、增殖和分化中具有已知作用，但 Smad4 突变体视网膜祖细胞能够在整个胚胎发育过程中维持生长和神经发生。我们还发现 Smad4 的缺失导致视网膜神经节细胞轴突向视神经头的异常靶向，这一表型与发育中的视网膜中 BMP 信号的减少一致。
这些结果表明 Smad4 对于 TGF-β/BMP 依赖性发育过程的胚胎视网膜中的一部分是必需的，但不是全部。此外，Smad4 在胚胎视网膜中的遗传要求主要表现在 TGF-β 信号通路的 BMP 分支调节的发育事件中。
