Journal Article

Functional interactions between alternatively spliced forms of Pax6 in crystallin gene regulation and in haploinsufficiency

Bharesh K. Chauhan, Ying Yang, Květa Cveklová and Aleš Cvekl

in Nucleic Acids Research

Volume 32, issue 5, pages 1696-1709
Published in print March 2004 | ISSN: 0305-1048
Published online March 2004 | e-ISSN: 1362-4962 | DOI: http://dx.doi.org/10.1093/nar/gkh334
Functional interactions between alternatively spliced forms of Pax6 in crystallin gene regulation and in haploinsufficiency

More Like This

Show all results sharing these subjects:

  • Chemistry
  • Biochemistry
  • Bioinformatics and Computational Biology
  • Genetics and Genomics
  • Molecular and Cell Biology

GO

Show Summary Details

Preview

Pax6 is essential for development of the eye, olfactory system, brain and pancreas. Haploinsufficiency of Pax6 causes abnormal eye development. Two forms of Pax6 protein, PAX6 and PAX6(5a), differ in a 14 amino acid insertion encoded by an alternatively spliced exon 5a in the N‐terminal DNA‐binding paired domain (PD), and they are simultaneously expressed. Here, we show that PAX6 and PAX6(5a) together synergistically activate transcription from promoters recognized by Pax6 PD and PD5a, but not by their homeodomain. This synergism promotes activation of transcription by c‐Maf and MafA on the αB‐crystallin promoter, and is required for transcriptional co‐activation by RARβ/RXRβ and PAX6/PAX6(5a) on the γF‐crystallin promoter. To determine the role of this synergism in haploinsufficiency, we tested four human missense (G18W, R26G, G64V and R128C) and one nonsense (R317X) mutants, with reporters driven by Pax6 PD consensus binding sites and the αB‐crystallin promoter. The simultaneous activity of Pax6 proteins [PAX6, mutated PAX6, PAX6(5a) and mutated PAX6(5a)] modeling haploinsufficiency yielded results not predicted by properties of individual PAX6 or PAX6(5a). Taken together, these results indicate that complex ocular phenotypes due to Pax6 haploinsufficiency originate, at least partially, from functional interactions between alternatively spliced PAX6 and PAX6(5a) variants and other factors, e.g. MafA/c‐Maf.

Journal Article.  8393 words.  Illustrated.

Subjects: Chemistry ; Biochemistry ; Bioinformatics and Computational Biology ; Genetics and Genomics ; Molecular and Cell Biology

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.