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
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Abstract
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.