Retinoic acid (RA), the acid derivative of vitamin A (MW = ~300) is a small molecule critical to eye development and lens regeneration. RA binds to two sets of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). The RARs have three isoforms, a, p and y (8 in the urodele amphibian). This binding activates the receptors, which are transcription factors that bind to retinoic acid response elements (RAREs) on the 5' side of target genes. Eye development is highly dependent on the activation by RA of the aB crystallin gene through its nuclear receptors, specifically the RAR-8 isoform of RAR (Tsonis et al., 2000). RAR-8 transcripts are expressed at low levels in the ganglion cell layer of the retina, but not elsewhere in the intact eye. After lentectomy, the RAR-8 gene is expressed in the dedifferentiated PECs that form the new lens vesicle, and expression increases to its highest level during new lens fiber differentiation (Tsonis et al., 2000).
The activation of the a B crystalline gene by RA signaling is also dependent on Pax-6, as shown by the fact that in mice mutated for Pax-6, RA signaling in the eye is decreased and the developing lens does not respond to exogenous RA (Enwright and Grainger, 2000). Inhibition of RA synthesis by disulfram, or inhibition of RAR function by the RAR antagonist 193109, results in the inhibition, retardation, or abnormal morphogenesis of the regenerating lens, although in some cases ectopic lenses regenerate from the ventral iris or the cornea (Tsonis et al., 2000). Collectively, these observations suggest that RARs and Pax-6 act together in promoting the differentiation of dedifferentiated dorsal iris cells to lens cells. However, elsewhere in the eye (ventral iris) RARs may function to inhibit ectopic lens regeneration.
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