Transcription Factors Regulating Lens Regeneration

A number of transcription factors are required for eye development. Among the most important is Pax-6, which is considered a master gene for eye development and is also required for development of the nervous

Lens Regeneration Amphibians
FIGURE 3.14 Regeneration of the newt lens. Pigmented cells of the dorsal iris (1) dedifferentiate to form unpigmented cells (2) that reform into a lens vesicle (3). The lens vesicle grows to fill the pupillary space as anterior epithelial cells differentiate into new lens fibers (4, 5).

53 Regeneration of Epidermal and Dental Tissues, Lens and Cornea system and the pancreas. Only cells that express Pax-6, Sox-2, and Six-3 can express lens crystallin genes (Cveki et al., 1995; Richardson et al., 1995; Del-Rio Tsonis et al., 1995; Oliver et al., 1995), suggesting that Pax-6 must act in combination with Sox-2 and Six-3 to activate these genes. The Pax-6 gene is expressed in the intact retina of the adult newt and in the cells of the regenerating lens vesicle at all stages of its development. Pax-6 expression is also observed in the developing retina and lens of the embryonic and larval axolotl, but declines as the axolotl gets older and becomes unable to regenerate its lens (Del-Rio Tsonis et al., 1995). A number of Hox genes appear to be downregulated in both the dorsal and ventral iris during newt lens regeneration (Jung et al., 1998). However, one Hox gene, prox-1, is upregulated specifically in the dorsal iris after lentec-tomy (Del-Rio Tsonis et al., 1999).

Since the dorsal iris or cornea does not regenerate lens unless the lens is removed, it has been proposed that the lens produces a signal or signals that normally inhibit iris or corneal cells from dedifferentiating (Reyer, 1977). Such signals have not yet been identified, but they might act through micropthalmic transcription factor (Mitf). Mitf encodes a basic helix-loop-helix (HLH) -leucine zipper transcription factor and is active in PECs, the ear and pigmented cells of the skin. The expression patterns of Pax-6 and mitf are complementary in chick embryo pigmented epithelial cells, both in vivo and in vitro. Overexpression of Mitf inhibits Fgf-2-induced transformation of cultured chick pigmented epithelial cells to lens cells and simultaneously inhibits expression of pax-6 (Mochii et al., 1998). Although not yet replicated in amphibians, these results suggest that the negative regulation of pax-6 by Mitf may be a crucial event in preventing dorsal iris cells from dedif-ferentiating and participating in lens regeneration.

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