Regulation of a remote Shh forebrain enhancer by the Six3 homeoprotein

Autores
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.
Año de publicación
2008
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
Fil: Jeong, Yongsu. University of Pennsylvania; Estados Unidos
Fil: Coluccio Leskow, Federico. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. University of Pennsylvania; Estados Unidos
Fil: El Jaick, Kenia. National Institutes of Health; Estados Unidos
Fil: Roessler, Erich. National Institutes of Health; Estados Unidos
Fil: Muenke, Maximilian. National Institutes of Health; Estados Unidos
Fil: Yocum, Anastasia. University of Pennsylvania; Estados Unidos
Fil: Dubourg, Christele. Universite de Rennes I; Francia
Fil: Li, Xue. Children’s Hospital of Boston; Estados Unidos
Fil: Geng, Xin. St. Jude Children’s Research Hospital; Estados Unidos
Fil: Oliver, Guillermo. St. Jude Children’s Research Hospital; Estados Unidos
Fil: Epstein, Douglas J.. University of Pennsylvania; Estados Unidos
Materia
Sonic Hedgehog
Mouse Development
Forebrain Enhancer
Six
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/83860
Acceder
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network_name_str CONICET Digital (CONICET)
spelling Regulation of a remote Shh forebrain enhancer by the Six3 homeoproteinJeong, YongsuColuccio Leskow, FedericoEl Jaick, KeniaRoessler, ErichMuenke, MaximilianYocum, AnastasiaDubourg, ChristeleLi, XueGeng, XinOliver, GuillermoEpstein, Douglas J.Sonic HedgehogMouse DevelopmentForebrain EnhancerSixhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1In 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.Fil: Jeong, Yongsu. University of Pennsylvania; Estados UnidosFil: Coluccio Leskow, Federico. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. University of Pennsylvania; Estados UnidosFil: El Jaick, Kenia. National Institutes of Health; Estados UnidosFil: Roessler, Erich. National Institutes of Health; Estados UnidosFil: Muenke, Maximilian. National Institutes of Health; Estados UnidosFil: Yocum, Anastasia. University of Pennsylvania; Estados UnidosFil: Dubourg, Christele. Universite de Rennes I; FranciaFil: Li, Xue. Children’s Hospital of Boston; Estados UnidosFil: Geng, Xin. St. Jude Children’s Research Hospital; Estados UnidosFil: Oliver, Guillermo. St. Jude Children’s Research Hospital; Estados UnidosFil: Epstein, Douglas J.. University of Pennsylvania; Estados UnidosNature Publishing Group2008-11info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/83860Jeong, 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; 1348-13531061-4036CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1038/ng.230info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/ng.230info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:03:31Zoai:ri.conicet.gov.ar:11336/83860instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 10:03:31.599CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Regulation of a remote Shh forebrain enhancer by the Six3 homeoprotein
title Regulation of a remote Shh forebrain enhancer by the Six3 homeoprotein
spellingShingle Regulation of a remote Shh forebrain enhancer by the Six3 homeoprotein
Jeong, Yongsu
Sonic Hedgehog
Mouse Development
Forebrain Enhancer
Six
title_short Regulation of a remote Shh forebrain enhancer by the Six3 homeoprotein
title_full Regulation of a remote Shh forebrain enhancer by the Six3 homeoprotein
title_fullStr Regulation of a remote Shh forebrain enhancer by the Six3 homeoprotein
title_full_unstemmed Regulation of a remote Shh forebrain enhancer by the Six3 homeoprotein
title_sort Regulation of a remote Shh forebrain enhancer by the Six3 homeoprotein
dc.creator.none.fl_str_mv 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.
author Jeong, Yongsu
author_facet 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.
author_role author
author2 Coluccio Leskow, Federico
El Jaick, Kenia
Roessler, Erich
Muenke, Maximilian
Yocum, Anastasia
Dubourg, Christele
Li, Xue
Geng, Xin
Oliver, Guillermo
Epstein, Douglas J.
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Sonic Hedgehog
Mouse Development
Forebrain Enhancer
Six
topic Sonic Hedgehog
Mouse Development
Forebrain Enhancer
Six
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv 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.
Fil: Jeong, Yongsu. University of Pennsylvania; Estados Unidos
Fil: Coluccio Leskow, Federico. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. University of Pennsylvania; Estados Unidos
Fil: El Jaick, Kenia. National Institutes of Health; Estados Unidos
Fil: Roessler, Erich. National Institutes of Health; Estados Unidos
Fil: Muenke, Maximilian. National Institutes of Health; Estados Unidos
Fil: Yocum, Anastasia. University of Pennsylvania; Estados Unidos
Fil: Dubourg, Christele. Universite de Rennes I; Francia
Fil: Li, Xue. Children’s Hospital of Boston; Estados Unidos
Fil: Geng, Xin. St. Jude Children’s Research Hospital; Estados Unidos
Fil: Oliver, Guillermo. St. Jude Children’s Research Hospital; Estados Unidos
Fil: Epstein, Douglas J.. University of Pennsylvania; Estados Unidos
description 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.
publishDate 2008
dc.date.none.fl_str_mv 2008-11
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/83860
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
url http://hdl.handle.net/11336/83860
identifier_str_mv 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
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1038/ng.230
info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/ng.230
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.885934

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