| First Author | Jeong Y | Year | 2008 |
| Journal | Nat Genet | Volume | 40 |
| Issue | 11 | Pages | 1348-53 |
| PubMed ID | 18836447 | Mgi Jnum | J:186828 |
| Mgi Id | MGI:5433287 | Doi | 10.1038/ng.230 |
| Citation | Jeong Y, et al. (2008) Regulation of a remote Shh forebrain enhancer by the Six3 homeoprotein. Nat Genet 40(11):1348-53 |
| abstractText | 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. |
