TY - JOUR
T1 - BMP inhibition-driven regulation of six-3 underlies induction of newt lens regeneration
AU - Grogg, Matthew W.
AU - Call, Mindy K.
AU - Okamoto, Mitsumasa
AU - Vergara, M. Natalia
AU - Del Rio-Tsonis, Katia
AU - Tsonis, Panagiotis A.
N1 - Funding Information:
Acknowledgements We thank T. Hayashi for sharing his expertise with the culturing methods for PECs; G. Oliver and D. Englecamp for the six-3 and pax-6 expression vectors, respectively; members of our laboratories, M. Metheney, A. Thitoff, S. Gainer, M. Tsavaris, M. Tubb and M. Sander for help with histology; V. Mitashov and E. Makarev for providing information on P.Waltl six-3 sequences; and E. Tanaka for information on axolotl BMPR-IA sequences. This work was supported by a grant from the NIH (to P.A.T.).
PY - 2005/12/8
Y1 - 2005/12/8
N2 - Lens regeneration in adult newts is a classic example of how cells can faithfully regenerate a complete organ through the process of transdifferentiation1-6. After lens removal, the pigment epithelial cells of the dorsal, but not the ventral, iris dedifferentiate and then differentiate to form a new lens. Understanding how this process is regulated might provide clues about why lens regeneration does not occur in higher vertebrates. The genes six-3 and pax-6 are known to induce ectopic lenses during embryogenesis7,8. Here we tested these genes, as well as members of the bone morphogenetic protein (BMP) pathway that regulate establishment of the dorsal-ventral axis in embryos9, for their ability to induce lens regeneration. We show that the lens can be regenerated from the ventral iris when the BMP pathway is inhibited and when the iris is transfected with six-3 and treated with retinoic acid. In intact irises, six-3 is expressed at higher levels in the ventral than in the dorsal iris. During regeneration, however, only expression in the dorsal iris is significantly increased. Such an increase is seen in ventral irises only when they are induced to transdifferentiate by six-3 and retinoic acid or by BMP inhibitors. These data suggest that lens regeneration can be achieved in noncompetent adult tissues and that this regeneration occurs through a gene regulatory mechanism that is more complex than the dorsal expression of lens regeneration-specific genes.
AB - Lens regeneration in adult newts is a classic example of how cells can faithfully regenerate a complete organ through the process of transdifferentiation1-6. After lens removal, the pigment epithelial cells of the dorsal, but not the ventral, iris dedifferentiate and then differentiate to form a new lens. Understanding how this process is regulated might provide clues about why lens regeneration does not occur in higher vertebrates. The genes six-3 and pax-6 are known to induce ectopic lenses during embryogenesis7,8. Here we tested these genes, as well as members of the bone morphogenetic protein (BMP) pathway that regulate establishment of the dorsal-ventral axis in embryos9, for their ability to induce lens regeneration. We show that the lens can be regenerated from the ventral iris when the BMP pathway is inhibited and when the iris is transfected with six-3 and treated with retinoic acid. In intact irises, six-3 is expressed at higher levels in the ventral than in the dorsal iris. During regeneration, however, only expression in the dorsal iris is significantly increased. Such an increase is seen in ventral irises only when they are induced to transdifferentiate by six-3 and retinoic acid or by BMP inhibitors. These data suggest that lens regeneration can be achieved in noncompetent adult tissues and that this regeneration occurs through a gene regulatory mechanism that is more complex than the dorsal expression of lens regeneration-specific genes.
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U2 - 10.1038/nature04175
DO - 10.1038/nature04175
M3 - Article
C2 - 16341014
AN - SCOPUS:28644448771
SN - 0028-0836
VL - 438
SP - 858
EP - 862
JO - Nature
JF - Nature
IS - 7069
ER -