Purchase this article with an account.
C. P. Tanzie, S. Chen, T. Xie; Notch2 Regulates Proliferation and Morphogenesis in the Developing Mouse Ciliary Body. Invest. Ophthalmol. Vis. Sci. 2010;51(13):6329.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Glaucoma is a leading cause of blindness worldwide. A common target of pharmacotherapy to treat this disease is the ciliary body. Despite a good understanding of the physiology of the ciliary body, the processes which regulate its development are still largely a mystery. Here we show how Notch2 regulates both the proliferation and morphogenesis of the ciliary body through a BMP dependent mechanism.
We use Cre-loxP technology to selectively knock-out the Notch2 receptor in the inner ciliary epithelium (ICE) of the ciliary body. A combination of immunohistochemistry, in-situ hybridization, and BrdU labeling of proliferative cells is used to characterize the mutant phenotype. To further analyze how Notch2 regulates this process we have performed a microarray to compare global gene expression changes between the wild-type and mutant ICEs.
The Notch2 mutant displays a complete lack of ciliary body morphogenesis. Our findings show that Notch2 regulates the proliferation, cell polarity, and cytoskeleton of the ciliary body to achieve proper morphogenesis, but it does not affect cell fate. At least one mechanism by which it accomplishes this is by affecting the phosphorylation of the receptor-activated Smad proteins and therefore the propagation of the BMP pathway, disruption of which has been shown to display a similar phenotype to the Notch2 mutant. Additionally, our bioinformatic analysis of the microarray data has found significant gene expression changes in cell-cycle regulators, the p53 pathway, and the TGF-beta pathway.
Previous studies have demonstrated a role for the BMP pathway in the development of the ciliary body. To our knowledge, we are the first to show that Notch2 plays a role in the development of the ciliary body, and that it does this, at least in part, by regulating the BMP pathway. These findings add important insight into our understanding of the development of both the ciliary body and anterior eye. It also demonstrates an additional link between the Notch and BMP pathways which may have relevance in many other systems involving these pathways.
This PDF is available to Subscribers Only