The temporal requirement for vitamin A in the developing eye: mechanism of action in optic fissure closure and new roles for the vitamin in regulating cell proliferation and adhesion in the embryonic retina

Dev Biol. 2009 Jan 1;325(1):94-105. doi: 10.1016/j.ydbio.2008.09.030. Epub 2008 Oct 14.


Mammalian eye development requires vitamin A (retinol, ROL). The role of vitamin A at specific times during eye development was studied in rat fetuses made vitamin A deficient (VAD) after embryonic day (E) 10.5 (late VAD). The optic fissure does not close in late VAD embryos, and severe folding and collapse of the retina is observed at E18.5. Pitx2, a gene required for normal optic fissure closure, is dramatically downregulated in the periocular mesenchyme in late VAD embryos, and dissolution of the basal lamina does not occur at the optic fissure margin. The addition of ROL to late VAD embryos by E12.5 restores Pitx2 expression, supports dissolution of the basal lamina, and prevents coloboma, whereas supplementation at E13.5 does not. Surprisingly, ROL given as late as E13.5 completely prevents folding of the retina despite the presence of an open fetal fissure, showing that coloboma and retinal folding represent distinct VAD-dependent defects. Retinal folding due to VAD is preceded by an overall reduction in the percentage of cyclin D1 positive cells in the developing retina, (initially resulting in retinal thinning), as well as a dramatic reduction in the cell adhesion-related molecules, N-cadherin and beta-catenin. Reduction of retinal cell number combined with a loss of the normal cell-cell adhesion proteins may contribute to the collapse and folding of the retina that occurs in late VAD fetuses.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Basement Membrane / drug effects
  • Basement Membrane / pathology
  • Cadherins / metabolism
  • Cell Adhesion / drug effects
  • Cell Death / drug effects
  • Cell Differentiation / drug effects
  • Cell Proliferation / drug effects
  • Coloboma / complications
  • Coloboma / embryology
  • Coloboma / genetics
  • Cyclin D1 / metabolism
  • Down-Regulation / drug effects
  • Embryo, Mammalian / abnormalities
  • Embryo, Mammalian / drug effects
  • Fetus / abnormalities
  • Fetus / drug effects
  • Gene Expression Regulation, Developmental / drug effects
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Retina / abnormalities
  • Retina / cytology*
  • Retina / drug effects
  • Retina / embryology*
  • Retinal Ganglion Cells / cytology
  • Retinal Ganglion Cells / drug effects
  • Time Factors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Vitamin A / metabolism*
  • Vitamin A / pharmacology
  • Vitamin A Deficiency / embryology
  • Vitamin A Deficiency / genetics
  • beta Catenin / metabolism


  • Cadherins
  • Homeodomain Proteins
  • RNA, Messenger
  • Transcription Factors
  • beta Catenin
  • Vitamin A
  • Cyclin D1
  • homeobox protein PITX2