Regulation of a remote Shh forebrain enhancer by the Six3 homeoprotein. - Archive ouverte HAL Access content directly
Journal Articles Nature Genetics Year : 2008

Regulation of a remote Shh forebrain enhancer by the Six3 homeoprotein.

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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.

Dates and versions

inserm-00353024 , version 1 (14-01-2009)

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Cite

Yongsu Jeong, Federico Coluccio Leskow, Kenia B. El-Jaick, Erich Roessler, Maximilian Muenke, et al.. Regulation of a remote Shh forebrain enhancer by the Six3 homeoprotein.. Nature Genetics, 2008, 40 (11), pp.1348-53. ⟨10.1038/ng.230⟩. ⟨inserm-00353024⟩
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