Direct interaction of geminin and Six3 in eye development

Nature. 2004 Feb 19;427(6976):745-9. doi: 10.1038/nature02292.


Organogenesis in vertebrates requires the tight control of cell proliferation and differentiation. The homeobox-containing transcription factor Six3 plays a pivotal role in the proliferation of retinal precursor cells. In a yeast two-hybrid screen, we identified the DNA replication-inhibitor geminin as a partner of Six3. Geminin inhibits cell-cycle progression by sequestering Cdt1 (refs 4, 5), the key component for the assembly of the pre-replication complex. Here, we show that Six3 efficiently competes with Cdt1 directly to bind to geminin, which reveals how Six3 can promote cell proliferation without transcription. In common with Six3 inactivation, overexpression of the geminin gene (Gem; also known as Gmn) in medaka (Oryzias latipes) induces specific forebrain and eye defects that are rescued by Six3. Conversely, loss of Gem (in common with gain of Six3 (ref. 1)) promotes retinal precursor-cell proliferation and results in expanded optic vesicles, markedly potentiating Six3 gain-of-function phenotypes. Our data indicate that the transcription factor Six3 and the replication-initiation inhibitor geminin act antagonistically to control the balance between proliferation and differentiation during early vertebrate eye development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding, Competitive
  • Brain / abnormalities
  • Brain / cytology
  • Brain / embryology
  • Brain / metabolism
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Death
  • Cell Differentiation
  • Cell Division
  • Eye / cytology
  • Eye / embryology*
  • Eye / metabolism*
  • Eye Proteins
  • Geminin
  • HeLa Cells
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Humans
  • In Situ Hybridization
  • Molecular Sequence Data
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Oryzias / embryology*
  • Oryzias / genetics
  • Oryzias / metabolism
  • Phenotype
  • Precipitin Tests
  • Protein Binding
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Substrate Specificity
  • Transfection
  • Two-Hybrid System Techniques
  • Xenopus Proteins
  • Xenopus laevis / genetics
  • Xenopus laevis / metabolism


  • Cell Cycle Proteins
  • Eye Proteins
  • GMNN protein, Xenopus
  • GMNN protein, human
  • Geminin
  • Homeodomain Proteins
  • Nerve Tissue Proteins
  • RNA, Messenger
  • Sine oculis homeobox homolog 3 protein
  • Xenopus Proteins

Associated data

  • GENBANK/AJ608707