We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Regulation of a remote Shh forebrain enhancer by the Six3 homeoprotein.
- Authors
Jeong, Yongsu; Leskow, Federico Coluccio; El-Jaick, Kenia; Roessler, Erich; Muenke, Maximilian; Yocum, Anastasia; Dubourg, Christele; Li, Xue; Geng, Xin; Oliver, Guillermo; Epstein, Douglas J
- Abstract
In humans, SHH haploinsufficiency results in holoprosencephaly (HPE), a defect in anterior midline formation. Despite the importance of maintaining SHH transcript levels above a critical threshold, we know little about the upstream regulators of SHH expression in the forebrain. Here we describe a rare nucleotide variant located 460 kb upstream of SHH in an individual with HPE that resulted in the loss of Shh brain enhancer-2 (SBE2) activity in the hypothalamus of transgenic mouse embryos. Using a DNA affinity-capture assay, we screened the SBE2 sequence for DNA-binding proteins and identified members of the Six3 and Six6 homeodomain family as candidate regulators of Shh transcription. Six3 showed reduced binding affinity for the mutant compared to the wild-type SBE2 sequence. Moreover, Six3 with HPE-causing alterations failed to bind and activate SBE2. These data suggest a direct link between Six3 and Shh regulation during normal forebrain development and in the pathogenesis of HPE.
- Subjects
PROSENCEPHALON; PROTEINS; HOLOPROSENCEPHALY; BRAIN; TRANSGENIC mice; LABORATORY mice; DNA
- Publication
Nature Genetics, 2008, Vol 40, Issue 11, p1348
- ISSN
1061-4036
- Publication type
Article
- DOI
10.1038/ng.230