NPPB and ACAN, two novel SHOX2 transcription targets implicated in skeletal development.

SHOX and SHOX2 transcription factors are highly homologous, with even identical homeodomains. Genetic alterations in SHOX result in two skeletal dysplasias; Léri-Weill dyschondrosteosis (LWD) and Langer mesomelic dysplasia (LMD), while no human genetic disease has been linked to date with SHOX2. SHO...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Miriam Aza-Carmona, Veronica Barca-Tierno, Alfonso Hisado-Oliva, Alberta Belinchón, Darya Gorbenko-del Blanco, Jose Ignacio Rodriguez, Sara Benito-Sanz, Angel Campos-Barros, Karen E Heath
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/89a138f2f118481c9cfa442111c15dd6
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:89a138f2f118481c9cfa442111c15dd6
record_format	dspace
spelling	oai:doaj.org-article:89a138f2f118481c9cfa442111c15dd62021-11-18T08:38:20ZNPPB and ACAN, two novel SHOX2 transcription targets implicated in skeletal development.1932-620310.1371/journal.pone.0083104https://doaj.org/article/89a138f2f118481c9cfa442111c15dd62014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24421874/?tool=EBIhttps://doaj.org/toc/1932-6203SHOX and SHOX2 transcription factors are highly homologous, with even identical homeodomains. Genetic alterations in SHOX result in two skeletal dysplasias; Léri-Weill dyschondrosteosis (LWD) and Langer mesomelic dysplasia (LMD), while no human genetic disease has been linked to date with SHOX2. SHOX2 is, though, involved in skeletal development, as shown by different knockout mice models. Due to the high homology between SHOX and SHOX2, and their functional redundancy during heart development, we postulated that SHOX2 might have the same transcriptional targets and cofactors as SHOX in limb development. We selected two SHOX transcription targets regulated by different mechanisms: 1) the natriuretic peptide precursor B gene (NPPB) involved in the endochondral ossification signalling and directly activated by SHOX; and 2) Aggrecan (ACAN), a major component of cartilage extracellular matrix, regulated by the cooperation of SHOX with the SOX trio (SOX5, SOX6 and SOX9) via the protein interaction between SOX5/SOX6 and SHOX. Using the luciferase assay we have demonstrated that SHOX2, like SHOX, regulates NPPB directly whilst activates ACAN via its cooperation with the SOX trio. Subsequently, we have identified and characterized the protein domains implicated in the SHOX2 dimerization and also its protein interaction with SOX5/SOX6 and SHOX using the yeast-two hybrid and co-immunoprecipitation assays. Immunohistochemistry of human fetal growth plates from different time points demonstrated that SHOX2 is coexpressed with SHOX and the members of the SOX trio. Despite these findings, no mutation was identified in SHOX2 in a cohort of 83 LWD patients with no known molecular defect, suggesting that SHOX2 alterations do not cause LWD. In conclusion, our work has identified the first cofactors and two new transcription targets of SHOX2 in limb development, and we hypothesize a time- and tissue-specific functional redundancy between SHOX and SHOX2.Miriam Aza-CarmonaVeronica Barca-TiernoAlfonso Hisado-OlivaAlberta BelinchónDarya Gorbenko-del BlancoJose Ignacio RodriguezSara Benito-SanzAngel Campos-BarrosKaren E HeathPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 1, p e83104 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Miriam Aza-Carmona Veronica Barca-Tierno Alfonso Hisado-Oliva Alberta Belinchón Darya Gorbenko-del Blanco Jose Ignacio Rodriguez Sara Benito-Sanz Angel Campos-Barros Karen E Heath NPPB and ACAN, two novel SHOX2 transcription targets implicated in skeletal development.
description	SHOX and SHOX2 transcription factors are highly homologous, with even identical homeodomains. Genetic alterations in SHOX result in two skeletal dysplasias; Léri-Weill dyschondrosteosis (LWD) and Langer mesomelic dysplasia (LMD), while no human genetic disease has been linked to date with SHOX2. SHOX2 is, though, involved in skeletal development, as shown by different knockout mice models. Due to the high homology between SHOX and SHOX2, and their functional redundancy during heart development, we postulated that SHOX2 might have the same transcriptional targets and cofactors as SHOX in limb development. We selected two SHOX transcription targets regulated by different mechanisms: 1) the natriuretic peptide precursor B gene (NPPB) involved in the endochondral ossification signalling and directly activated by SHOX; and 2) Aggrecan (ACAN), a major component of cartilage extracellular matrix, regulated by the cooperation of SHOX with the SOX trio (SOX5, SOX6 and SOX9) via the protein interaction between SOX5/SOX6 and SHOX. Using the luciferase assay we have demonstrated that SHOX2, like SHOX, regulates NPPB directly whilst activates ACAN via its cooperation with the SOX trio. Subsequently, we have identified and characterized the protein domains implicated in the SHOX2 dimerization and also its protein interaction with SOX5/SOX6 and SHOX using the yeast-two hybrid and co-immunoprecipitation assays. Immunohistochemistry of human fetal growth plates from different time points demonstrated that SHOX2 is coexpressed with SHOX and the members of the SOX trio. Despite these findings, no mutation was identified in SHOX2 in a cohort of 83 LWD patients with no known molecular defect, suggesting that SHOX2 alterations do not cause LWD. In conclusion, our work has identified the first cofactors and two new transcription targets of SHOX2 in limb development, and we hypothesize a time- and tissue-specific functional redundancy between SHOX and SHOX2.
format	article
author	Miriam Aza-Carmona Veronica Barca-Tierno Alfonso Hisado-Oliva Alberta Belinchón Darya Gorbenko-del Blanco Jose Ignacio Rodriguez Sara Benito-Sanz Angel Campos-Barros Karen E Heath
author_facet	Miriam Aza-Carmona Veronica Barca-Tierno Alfonso Hisado-Oliva Alberta Belinchón Darya Gorbenko-del Blanco Jose Ignacio Rodriguez Sara Benito-Sanz Angel Campos-Barros Karen E Heath
author_sort	Miriam Aza-Carmona
title	NPPB and ACAN, two novel SHOX2 transcription targets implicated in skeletal development.
title_short	NPPB and ACAN, two novel SHOX2 transcription targets implicated in skeletal development.
title_full	NPPB and ACAN, two novel SHOX2 transcription targets implicated in skeletal development.
title_fullStr	NPPB and ACAN, two novel SHOX2 transcription targets implicated in skeletal development.
title_full_unstemmed	NPPB and ACAN, two novel SHOX2 transcription targets implicated in skeletal development.
title_sort	nppb and acan, two novel shox2 transcription targets implicated in skeletal development.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/89a138f2f118481c9cfa442111c15dd6
work_keys_str_mv	AT miriamazacarmona nppbandacantwonovelshox2transcriptiontargetsimplicatedinskeletaldevelopment AT veronicabarcatierno nppbandacantwonovelshox2transcriptiontargetsimplicatedinskeletaldevelopment AT alfonsohisadooliva nppbandacantwonovelshox2transcriptiontargetsimplicatedinskeletaldevelopment AT albertabelinchon nppbandacantwonovelshox2transcriptiontargetsimplicatedinskeletaldevelopment AT daryagorbenkodelblanco nppbandacantwonovelshox2transcriptiontargetsimplicatedinskeletaldevelopment AT joseignaciorodriguez nppbandacantwonovelshox2transcriptiontargetsimplicatedinskeletaldevelopment AT sarabenitosanz nppbandacantwonovelshox2transcriptiontargetsimplicatedinskeletaldevelopment AT angelcamposbarros nppbandacantwonovelshox2transcriptiontargetsimplicatedinskeletaldevelopment AT kareneheath nppbandacantwonovelshox2transcriptiontargetsimplicatedinskeletaldevelopment
_version_	1718421513181331456

NPPB and ACAN, two novel SHOX2 transcription targets implicated in skeletal development.

Ejemplares similares