BMP signaling mediates stem/progenitor cell-induced retina regeneration

doi:10.1073/pnas.0708202104

BMP signaling mediates stem/progenitor cell-induced retina regeneration

*Department of Zoology, Miami University, Oxford, OH 45056; and
^†Laboratory of Molecular Biology, Department of Biology, University of Dayton, Dayton, OH 45469

Edited by Mark T. Keating, Novartis Institutes for Biomedical Research, Cambridge, MA, and approved October 24, 2007 (received for review September 1, 2007)

Abstract

We identified a mechanism whereby retina regeneration in the embryonic chick can be induced by the contribution of stem/progenitor cells. We show that bone morphogenetic protein (BMP) signaling is sufficient and necessary to induce retina regeneration and that its action can be divided into two phases. By 3 days after postretinectomy (d PR), the BMP pathway directs proliferation and regeneration through the activation of Smad (canonical BMP pathway) and the up-regulation of FGF signaling by the MAPK pathway. By 7d PR, it induces apoptosis by activating p38 (a noncanonical BMP pathway) and down-regulating FGF signaling (by both MAPK and AKT pathways). Apoptosis at this later stage can be prevented, and BMP-induced regeneration can be further induced by inhibition of p38. These results unravel a mechanism for stem/progenitor cell-mediated retina regeneration, where BMP activation establishes a cross-talk with the FGF pathway and selectively activates the canonical and noncanonical BMP pathways. Retina stem/progenitor cells exist in other species, including humans. Thus, our findings provide insights on how retinal stem cells can be activated for possible regenerative therapies.

Footnotes

^‡To whom correspondence should be addressed. E-mail: delriok{at}muohio.edu
Author contributions: T.H., P.A.T., and K.D.R.-T. designed research; T.H., C.G., and J.-C.A. performed research; P.A.T. contributed new reagents/analytic tools; T.H., C.G., P.A.T., and K.D.R.-T. analyzed data; and T.H., P.A.T., and K.D.R.-T. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0708202104/DC1.