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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
11
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pubmed:dateCreated |
2008-10-29
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pubmed: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.
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pubmed:grant |
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/18836447-10369266,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18836447-10473118,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18836447-11152636,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18836447-11788837,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18836447-12050133,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18836447-12130660,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18836447-12163408,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18836447-12441302,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18836447-12569128,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18836447-12642481,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18836447-14581620,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18836447-14973488,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18836447-14980218,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18836447-15107405,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18836447-15314685,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18836447-15371303,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18836447-15705856,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18836447-15829955,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18836447-15973738,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18836447-15979605,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18836447-16005423,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18836447-16251966,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18836447-16407397,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18836447-16988653,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18836447-17066077,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18836447-17274816,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18836447-17392801,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18836447-17618282,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18836447-8837770,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18836447-8896572,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18836447-9226442
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Nov
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pubmed:issn |
1546-1718
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pubmed:author |
pubmed-author:DoreTT,
pubmed-author:DubourgChristeleC,
pubmed-author:El-JaickKeniaK,
pubmed-author:EpsteinDouglas JDJ,
pubmed-author:JeongYongsuY,
pubmed-author:LeskowFederico ColuccioFC,
pubmed-author:LiXueX,
pubmed-author:MuenkeMaximilianM,
pubmed-author:OliverGuillermoG,
pubmed-author:RoesslerErichE,
pubmed-author:YocumAnastasiaA
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pubmed:issnType |
Electronic
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pubmed:volume |
40
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1348-53
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pubmed:dateRevised |
2011-2-4
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pubmed:meshHeading |
pubmed-meshheading:18836447-Animals,
pubmed-meshheading:18836447-Base Sequence,
pubmed-meshheading:18836447-COS Cells,
pubmed-meshheading:18836447-Cercopithecus aethiops,
pubmed-meshheading:18836447-Eye Proteins,
pubmed-meshheading:18836447-Hedgehog Proteins,
pubmed-meshheading:18836447-Holoprosencephaly,
pubmed-meshheading:18836447-Homeodomain Proteins,
pubmed-meshheading:18836447-Humans,
pubmed-meshheading:18836447-Hypothalamus,
pubmed-meshheading:18836447-Mice,
pubmed-meshheading:18836447-Molecular Sequence Data,
pubmed-meshheading:18836447-Mutation,
pubmed-meshheading:18836447-Nerve Tissue Proteins,
pubmed-meshheading:18836447-Protein Binding,
pubmed-meshheading:18836447-Trans-Activators
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pubmed:year |
2008
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pubmed:articleTitle |
Regulation of a remote Shh forebrain enhancer by the Six3 homeoprotein.
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pubmed:affiliation |
Department of Genetics, University of Pennsylvania School of Medicine, 415 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural,
Research Support, N.I.H., Intramural
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