The demonstration of the role of hsf4 in the development of the lens was provided by the very elegant study of Akira Nakai's group (Fujimoto et al. 2004). HSF4 is expressed in both epithelial and fiber cells. Hsf4-null mice are viable, fertile, have the same weight as the wild-type animals, and exhibit no major abnormalities of the brain, lung, testis, or ovary. The animals suffer from cataract. The lens fiber cells contain inclusion-like structures rich in aA-and aB-crystallins, which can be detected as early as 2 days after birth. The authors show that the main direct targets of HSF4 are the y-crystallin genes. But HSF4 also represses the fgf (1 and 4) gene expression in epithelial cells, which proliferate in its absence, whereas HSF1 has an opposite effect. In the doublenull animals, the level of expression of FGFs and the number of epithelial cells returns to normal, demonstrating the antagonistic effects of HSF1 and HSF4 anticipated by Zhang et al. (2001), and suggesting a contrario a role so far not seen for HSF1 in the formation of the lens (and of other tissues such as the lung).
This study demonstrates the complexity of interactions between different HSFs: antagonistic for the expression of FGFs or some Hsps, but synergistic for the expression of y-crystallins. In addition, it shows that the definition of the different forms of HSFs as inhibitors or activators has only a limited value. The complementary study of Nahid Mivechi's group confirmed the involvement of HSF4 in lens development, but attributed it to the regulation of the 25-kDa heat shock protein (Min et al. 2004).
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