Regulation of AP-2 and apoptosis in developing eye in a vitamin A-deficiency model.
BACKGROUND
Eye malformations induced by vitamin A deficiency (VAD) during pregnancy is a major part of the VAD syndrome. But the signaling role of retinoic acid (RA) in ocular tissues is poorly understood. The goal of this study was to determine the role of retinoic acid receptor (RAR) in the development of eye and the possible signaling pathway.


METHODS
Time-pregnant mice were treated with 1 mg/kg dose of RAR antagonist AGN193109 (AGN) on 8 days postcoitum (dpc). Newborn mice and 18-dpc embryos were used for phenotype studies. Embryonic eyes of 18 dpc were sectioned for histological study. With immunohistochemistry and TUNEL method, we monitored the alternation of AP-2 expression and apoptotic cells in sections of 12- to 18-dpc embryos.


RESULTS
Treatment with AGN resulted in severe craniofacial and eye malformations in virtually all exposed fetuses. The ocular abnormalities included severe defects in anterior segments such as focal corneal thickening and eversion, absence of corneal endothelium and anterior chamber, differentiation defects of lens, as well as defects in posterior segment such as persistent hyperplastic primary vitreous and retinal eversions. The percentage of AP-2-positive cells in ocular tissues on 12, 14, and 18 dpc was significantly (P < 0.05) reduced in AGN-treated eyes compared to control ones. Additionally, the number of apoptotic cell was significantly (P < 0.05) increased in AGN-treated eyes.


CONCLUSIONS
The blocking of RAR function can lead to ocular abnormalities that depict partial phenocopies of vitamin A-deficiency syndrome. Both an inhibition of expression of AP-2 and an enhancement of cell death contribute to AGN-induced ocular defects.
Department of Pathology, Anatomy, and Cell Biology, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA.
Jian
J
Zhou
Devendra M
DM
Kochhar
D033962:Adaptor Protein Complex 2 / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D005124:Eye Abnormalities / Q000196:embryology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D008297:Male; D008431:Maternal-Fetal Exchange; D051379:Mice; D008809:Mice, Inbred C3H; D009024:Morphogenesis / Q000235:genetics; D009281:Naphthalenes / Q000494:pharmacology; D011247:Pregnancy; D011248:Pregnancy Complications; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors / Q000502:physiology*; D014802:Vitamin A Deficiency / Q000196:embryology
D033962:Adaptor Protein Complex 2; D009281:Naphthalenes; D018168:Receptors, Retinoic Acid; C096920:AGN 193109