Regulation of a remote Shh forebrain enhancer by the Six3 homeoprotein

Yongsu Jeong, Federico Coluccio Leskow, Kenia El-Jaick, Erich Roessler, Maximilian Muenke, Anastasia Yocum, Christele Dubourg, Xue Li, Xin Geng, Guillermo Oliver, Douglas J. Epstein

Research output: Contribution to journalArticlepeer-review

127 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1348-1353
Number of pages6
JournalNature Genetics
Issue number11
StatePublished - Nov 2008

ASJC Scopus subject areas

  • Genetics

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