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T. Haynes, C. Gutierrez, J.-C. Aycinena, P. Tsonis, K. Del Rio-Tsonis; BMP Induces Retinal Progenitor Cells to Participate in Retina Regeneration. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4087.
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The embryonic chick is able to regenerate a complete neural retina after retinectomy by activation of retinal progenitor cells (RPCs) present in the anterior margin of the eye. It has been determined that exogenous factors such as Fibroblast growth factor (FGF) or Sonic hedgehog (Shh) are sufficient to induce the RPCs to give rise to a new retina. In this work, we investigate the role of the bone morphogenetic protein (BMP) pathway in the activation of RPCs.
Embryonic day 4 (E4) chick retinas were removed and retroviruses designed to inhibit (RCAS noggin) or activate (RCAS BMPRIA) the BMP pathway were injected into the eye cavity. The disruption of the BMP pathway was tested in the presence and absence of a functional FGF pathway. Regeneration was assayed 3 and 7 days post-retinectomy. Differentiation of cell types and proliferation was determined by immunohistochemistry and the level of cell death was determined by TUNEL analysis.
Overexpression of the BMP receptor, BMPRIA, in the absence of an exogenous FGF pathway results in high proliferation of the RPCs and differentiation of all retinal cell types. However, a high level of apoptosis is also induced at 3 (E7) and 7 (E11) days post-retinectomy resulting in a decrease in regeneration by E11. The addition of ectopic FGF2 along with RCAS BMPRIA results in an increase in regeneration from the anterior margin and an expansion of the RPCs with no increase in apoptosis at E7 suggesting FGF2 plays a role in cell survival at this stage. By E11, there is an increase in apoptosis, especially in the anterior margin, in eyes treated with RCAS BMPRIA + FGF2 as the expanded RPCs begin to die. Inhibiting the BMP pathway by overexpressing noggin in the presence of FGF2 results in a decrease in regeneration from the anterior margin and a significant reduction in the number of RPCs. Differentiation of all cell types occurs when BMPRIA is overexpressed with FGF2, however, there is an increase in the number of ganglion, bipolar, and amacrine cells and Muller Glia cells are disorganized. Overexpressing noggin affects differentiation even when FGF2 is present with only photoreceptors and Muller Glia cells present in significant numbers suggesting BMP is important for differentiation of the RPCs as well.
These results suggest that the BMP pathway is able to induce proliferation, differentiation, and apoptosis of RPCs. The cellular response regulated by BMP is dependent on the presence of a functional FGF pathway.
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