An everted repeat mediates retinoic acid induction of the gamma F-crystallin gene: evidence of a direct role for retinoids in lens development.
The vertebrate lens is a classical system for examining mechanisms of tissue determination and differentiation, yet little is known about the signaling molecules controlling its development. Here, we report that retinoic acid (RA), a substance known for its teratogenic effects on the eye and as a natural endogenous morphogenetic agent, acts as a regulator of gene expression in the lens. We have identified a novel type of RA response element (RARE) within the lens-specific mouse gamma F-crystallin promoter, consisting of two (A/G)GGTCA motifs in an everted arrangement spaced by 8 nucleotides. This element (gamma F-RARE) mediates activation of the gamma F-crystallin promoter by ligand-activated endogenous lens cell RA receptors (RARs) and confers RA responsiveness when linked to a heterologous promoter. gamma F-RARE is bound in vitro by RAR/RXR heterodimers, and both receptors cooperate in vivo to trans-activate this element. These observations demonstrate a direct effect of RA on lens-specific gene expression and reveal a novel role for retinoids in the development and homeostasis of the mammalian eye.
Tini
M
M
Division of Endocrinology, Hospital for Sick Children, Toronto, Ontario, Canada.
Otulakowski
G
G
Breitman
M L
ML
Tsui
L C
LC
Giguère
V
V
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002642:Chick Embryo; D003459:Crystallins / Q000235:genetics*; D007908:Lens, Crystalline / Q000196:embryology*; D051379:Mice; D008969:Molecular Sequence Data; D012091:Repetitive Sequences, Nucleic Acid; D014212:Tretinoin / Q000378:metabolism*
D003459:Crystallins; D014212:Tretinoin