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  Mutually regulated expression of Pax6 and Six3 and its implications for the Pax6 haploinsufficient lens phenotype

Goudreau, G., Petrou, P., Reneker, L. W., Graw, J., Loster, J., & Gruss, P. (2002). Mutually regulated expression of Pax6 and Six3 and its implications for the Pax6 haploinsufficient lens phenotype. Proceedings of the National Academy of Sciences of the United States of America, 99(13), 8719-8724. Retrieved from http://www.pnas.org/content/99/13/8719.full.pdf+html.

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Goudreau, G.1, Autor           
Petrou, P.1, Autor           
Reneker, L. W., Autor
Graw, J., Autor
Loster, J., Autor
Gruss, P.1, Autor           
Affiliations:
1Department of Molecular Cell Biology, MPI for biophysical chemistry, Max Planck Society, ou_578585              

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Schlagwörter: homeodomain proteins; transcription factors; eye development
 Zusammenfassung: Pax6 is a key regulator of eye development in vertebrates and invertebrates, and heterozygous loss-of-function mutations of the mouse Pax6 gene result in the Small eye phenotype, in which a small lens is a constant feature. To provide an understanding of the mechanisms underlying this haploinsufficient phenotype, we evaluated in Pax6 heterozygous mice the effects of reduced Pax6 gene dosage on the activity of other transcription factors regulating eye formation. We found that Six3 expression was specifically reduced in lenses of Pax6 heterozygous mouse embryos. Interactions between orthologous genes from the Pax and Six families have been identified in Drosophila and vertebrate species, and we examined the control of Pax6 and Six3 gene expression in the developing mouse lens. Using in vitro and transgenic approaches, we found that either transcription factor binds regulatory sequences from the counterpart gene and that both genes mutually activate their expression. These studies define a functional relationship in the lens in which Six3 expression is dosage-dependent on Pax6 and where, conversely, Six3 activates Pax6. Accordingly, we show a rescue of the Pax6 haploinsufficient lens phenotype after lens-specific expression of Six3 in transgenic mice. This phenotypic rescue was accompanied by cell proliferation and activation of the platelet-derived growth factor alpha-R/cyclin D1 signaling pathway. Our findings thus provide a mechanism implicating gene regulatory interactions between Pax6 and Six3 in the tissue-specific defects found in Pax6 heterozygous mice.

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Sprache(n): eng - English
 Datum: 2002-06-25
 Publikationsstatus: Erschienen
 Seiten: -
 Ort, Verlag, Ausgabe: -
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 Art der Begutachtung: Expertenbegutachtung
 Identifikatoren: eDoc: 16503
URI: http://www.pnas.org/content/99/13/8719.full.pdf+html
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Titel: Proceedings of the National Academy of Sciences of the United States of America
Genre der Quelle: Zeitschrift
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Ort, Verlag, Ausgabe: -
Seiten: - Band / Heft: 99 (13) Artikelnummer: - Start- / Endseite: 8719 - 8724 Identifikator: -