Lens Induction and Development
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 | Endogenous lens and ectopic lenses in Xenopus tadpole derived from an embryo injected with RNA encoding Pax6. |
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 | Ectopic eyes (A, white arrow) form in Xenopus tadpoles from embryos misexpressing Pax6. Different markers for lens and retina can be identified in ectopic eyes (B) as in wild-type eyes(C). |
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 | The expression activity of the Pax6 gene lens enhancer is restricted to the presumptive lens ectoderm (blue labeled area) at 9.5 days of gestation in the mouse. |
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 | Model describing the genetic regulation of lens induction in the mouse. |
The optic cup ablation experiments of Hans Spemann (1901) provided the first experimental evidence to support the hypothesis that lens formation depends on signals received from adjacent cells. More recent experiments have shown that lens induction is likely to be a complex, multistage process. We have been focusing on trying to understand the induction process in molecular detail.
We have shown that the paired class transcription factor Pax6 plays a critical role in lens induction by using a misexpression strategy in the frog Xenopus laevis. When Pax6 is widely expressed in the developing Xenopus embryo, ectopic lenses are formed throughout he head region (Altmann et al., 1997). In related work (Chow et al., 1999) we have shown that misexpression of Pax6 can direct the formation of whole ectopic eyes in a vertebrate. This extends the work of other investigators showing that Pax6 from different species has the ability to direct eye formation in Drosophila (Halder et al., 1995). Combined with the demonstration that in Drosophila and mammals, mutations in Pax6 result in eye deficiencies, these experiments support the idea that Pax6 is a critical early regulator of eye development and that it lies at the apex of a genetic pathway regulating eye development.
These experiments indicated that an understanding of the regulation of the Pax6 gene would be critical for an understanding of lens induction. For this reason, we recently took steps to identify transcriptional control elements from Pax6 that were functional in lens lineage cells and identified a 341 bp enhancer that activates gene expression in the early presumptive lens ectoderm (Williams et al., 1998). The important role of this enhancer in lens induction and development was illustrated by the lens development delay and microophthalmia resulting when the enhancer was deleted in gene-targeted mice (Dimanlig et al, 2001). Examination of marker gene expression in enhancer deleted mice has also allowed us to show that the gene FoxE3 (mutated in the dysgenetic lens mouse) is genetically downstream.
The Spemann optic cup ablation experiments taught us that signaling interactions between the optic vesicle and presumptive lens ectoderm are critical for initiating lens development. We have recently investigated the nature of the signaling interaction. First, we have shown using both transgenic mouse and explant culture strategies, that signaling through a fibroblast growth factor (Fgf) receptor plays an important role in lens induction (Faber et al., 2001).
Expression of a dominant-negative form of FgfR1IIIc in the presumptive lens ectoderm resulted in a delay in the formation of the lens placode and failure of the lens vesicle to separate from the surface ectoderm. This implies that Fgf receptor function is required at inductive phases of lens development. Second, we determined whether Fgf receptor activity and Bmp7 signaling (an established lens induction signal) might cooperate in lens induction by performing crosses between mutant mouse lines and assessing the phenotype resulting. This showed that Fgf receptor and Bmp7 signaling combine to permit the full level of Pax6 expression in the lens placode. This and other experiments has allowed us to propose a model describing the genetic regulation of lens induction in the mouse (Chow and Lang, 2001; Triesman and Lang, 2002). In our current analyses, we are further investigating the inductive signal exchange between presumptive lens and presumptive retina by assessing the need for signaling responses besides those of the Fgf and Bmp pathways.
How to Reach Us
The Lang Laboratory is part of the Division of Developmental Biology at Cincinnati Children's Research Foundation. The lab is located in Location R (Research Foundation Building), Room 1447.
Related Publications
Where possible, article titles are linked to an abstract of the article. Selected citations may also be linked to PDFs of the article available on a Journal's site. Depending on the Journal's publishing policy, you may need a subscription to download the PDF.
R. Chow, G. Diez-Roux, M. Roghani, M. Palmer, D. Rifkin, D. Moscatelli and R.A. Lang. (1995). FGF suppresses apoptosis and induces differentiation of fibre cells in the mouse lens. Development, 121, 4383- 4393.
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C.R. Altmann, R.L. Chow, R.A. Lang and A. Hemmati-Brivanlou (1997). Lens induction by Pax-6 in Xenopus laevis. Developmental Biology, 185, 119-123.
S.C. Williams, C.R. Altmann, R.L. Chow, A. Hemmati-Brivanlou and R.A. Lang (1998). A highly conserved lens transcriptional control element from the Pax-6 gene. Mech. Development, 7, 225-229.
A.T. Ogden, I. Nunes, K. Ko, S. Wu, C. Hines, R. Hegde and R.A. Lang (1998). GRIFIN, a novel lens- specific protein related to the galectin family. J. Biological Chemistry, 273, 28889-28896.
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R.L. Chow, C.R. Altmann, R.A. Lang and A. Hemmati-Brivanlou (1999). Pax6 induces ectopic eyes in a vertebrate. Development, 126, 4213-4222.
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R.A. Lang. Which factors mediate lens fiber cell differentiation in vivo ? (1999). Investigative Ophthalmology and Visual Science, 40, 3075-3078.
S. Shirke, M. Hallem, M. Robinson, P. Overbeek and R.A. Lang. (2001) Misexpression of IGF-I can perturb polarization of the lens. Mechanisms of Development, 101, 167-174.
R. Chow and R.A. Lang. Early development of the vertebrate eye (2001) (invited review). Annual Reviews in Cell and Developmental Biology, 17, 255-296.
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P. Dimanlig, S.C. Faber, W. Auerbach, H.P. Makarenkova, and R.A. Lang (2001). The upstream ectoderm enhancer in Pax6 has an important role in lens induction. Development, 128, 4415-4424.
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S. Faber, H.P. Makarenkova, P. Dimanlig, S. Shirke, K.O. Ko and R.A. Lang (2001). Fgf receptor signaling plays an important role in lens induction. Development, 128, 4425-4438.
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J. Treisman and R.A. Lang (2002). Development and Evolution of the Eye; A meeting report from Fondation des Treilles. Mechanisms of Development, 112, 3-8.
S. Faber, M. Robinson, H. Makarenkova and R.A. Lang (2002). BMP signaling is required for primary lens fiber cell differentiation. Development, 129, 3727-3737.
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