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L. Musil, B. Boswell, P. Overbeek; In vivo Role of BMP Signaling in Lens Cell Differentiation. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1137. doi: https://doi.org/.
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Cultures of embryonic chick lens epithelial cells upregulate expression of the fiber differentiation markers delta crystallin and CP49 in response to FGF 1/2 or to medium conditioned by intact vitreous bodies, the major reservoir of diffusible factors (including FGF) for the lens equator in vivo. We have also shown that vitreous contains diffusible BMP bioactivity, and that abolishing BMP 2/4/7 signaling with the highly specific blocker noggin inhibits the ability of vitreous body conditioned medium to upregulate fiber marker expression. Noggin and other specific BMP blockers also reduce the ability of FGF (but not of unrelated stimuli such as serum or 8-CPT) to increase fiber marker expression in these cultures. Here, we address whether noggin blocks fiber formation in the mammalian lens in vivo.
Biochemical and histological techniques were employed to characterize epithelial-to-secondary fiber differentiation in a previously generated strain of transgenic mice in which noggin is exogenously overexpressed under the control of the lens-specific alpha A crystallin promoter (Zhao et al., 2002 Development). Importantly, this promoter becomes active after formation of the lens placode and primary fiber cells, the stages in lens development already established to require noggin-sensitive BMP signaling.
There were no major differences in the total [35S]methionine-proteins metabolically labeled in freshly isolated transgenic and wild-type littermate lenses at P7. By P14, the transgenic eyes and lenses were markedly smaller than in the controls. This was accompanied by a striking change in the pattern of lens proteins produced: whereas bands migrating at ≥ 40 kD were synthesized at wild-type levels, de novo production of the fiber-specific alpha, beta, and gamma crystallins was severely depressed. Although the equatorial region of the noggin-overexpressing lenses was histologically relatively normal at P7, by day 14 the bow pattern was no longer present in the most peripheral fibers. Instead, the monolayer of cuboidal, undifferentiated epithelial cells extended to the posterior pole of the organ. As previously reported, morphological abnormalities were also detected in certain other ocular tissues (e.g., ciliary body).
Inhibiting BMP2/4/7 signaling in the lenticular environment in vivo abolishes secondary fiber differentiation. Although it is not yet known whether this is a direct result of impaired BMP signaling in the lens itself, these findings support our hypothesis that BMPs play a central role in secondary fiber formation.
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