info:eu-repo/semantics/article
Regulation of a remote Shh forebrain enhancer by the Six3 homeoprotein
Fecha
2008-11Registro en:
Jeong, Yongsu; Coluccio Leskow, Federico; El Jaick, Kenia; Roessler, Erich; Muenke, Maximilian; et al.; Regulation of a remote Shh forebrain enhancer by the Six3 homeoprotein; Nature Publishing Group; Nature Genetics; 40; 11; 11-2008; 1348-1353
1061-4036
CONICET Digital
CONICET
Autor
Jeong, Yongsu
Coluccio Leskow, Federico
El Jaick, Kenia
Roessler, Erich
Muenke, Maximilian
Yocum, Anastasia
Dubourg, Christele
Li, Xue
Geng, Xin
Oliver, Guillermo
Epstein, Douglas J.
Resumen
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.