BMP inhibition-driven regulation of six-3 underlies induction of newt lens regeneration

Nature. 2005 Dec 8;438(7069):858-62. doi: 10.1038/nature04175.


Lens regeneration in adult newts is a classic example of how cells can faithfully regenerate a complete organ through the process of transdifferentiation. 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 embryogenesis. 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 embryos, 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Ambystoma
  • Animals
  • Bone Morphogenetic Protein Receptors, Type I / genetics
  • Bone Morphogenetic Protein Receptors, Type I / metabolism
  • Bone Morphogenetic Proteins / antagonists & inhibitors*
  • Bone Morphogenetic Proteins / metabolism
  • Cell Differentiation / drug effects
  • Eye Proteins / genetics
  • Eye Proteins / metabolism*
  • Gene Expression Regulation, Developmental
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Iris / cytology
  • Iris / drug effects
  • Iris / growth & development
  • Iris / physiology
  • Lens, Crystalline / cytology
  • Lens, Crystalline / drug effects
  • Lens, Crystalline / growth & development
  • Lens, Crystalline / physiology*
  • Molecular Sequence Data
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • PAX6 Transcription Factor
  • Paired Box Transcription Factors / genetics
  • Paired Box Transcription Factors / metabolism
  • Pigment Epithelium of Eye / cytology
  • Pigment Epithelium of Eye / drug effects
  • Pigment Epithelium of Eye / metabolism
  • Regeneration / drug effects
  • Regeneration / physiology*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Salamandridae / genetics
  • Salamandridae / physiology*
  • Tretinoin / pharmacology


  • Bone Morphogenetic Proteins
  • Eye Proteins
  • Homeodomain Proteins
  • Nerve Tissue Proteins
  • PAX6 Transcription Factor
  • Paired Box Transcription Factors
  • Repressor Proteins
  • Sine oculis homeobox homolog 3 protein
  • Tretinoin
  • Bone Morphogenetic Protein Receptors, Type I

Associated data

  • GENBANK/AY795966
  • GENBANK/AY799802