Cargando…

Lhx1 functions together with Otx2, Foxa2, and Ldb1 to govern anterior mesendoderm, node, and midline development

Gene regulatory networks controlling functional activities of spatially and temporally distinct endodermal cell populations in the early mouse embryo remain ill defined. The T-box transcription factor Eomes, acting downstream from Nodal/Smad signals, directly activates the LIM domain homeobox transc...

Descripción completa

Detalles Bibliográficos
Autores principales: Costello, Ita, Nowotschin, Sonja, Sun, Xin, Mould, Arne W., Hadjantonakis, Anna-Katerina, Bikoff, Elizabeth K., Robertson, Elizabeth J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4617976/
https://www.ncbi.nlm.nih.gov/pubmed/26494787
http://dx.doi.org/10.1101/gad.268979.115
_version_ 1782396867522330624
author Costello, Ita
Nowotschin, Sonja
Sun, Xin
Mould, Arne W.
Hadjantonakis, Anna-Katerina
Bikoff, Elizabeth K.
Robertson, Elizabeth J.
author_facet Costello, Ita
Nowotschin, Sonja
Sun, Xin
Mould, Arne W.
Hadjantonakis, Anna-Katerina
Bikoff, Elizabeth K.
Robertson, Elizabeth J.
author_sort Costello, Ita
collection PubMed
description Gene regulatory networks controlling functional activities of spatially and temporally distinct endodermal cell populations in the early mouse embryo remain ill defined. The T-box transcription factor Eomes, acting downstream from Nodal/Smad signals, directly activates the LIM domain homeobox transcription factor Lhx1 in the visceral endoderm. Here we demonstrate Smad4/Eomes-dependent Lhx1 expression in the epiblast marks the entire definitive endoderm lineage, the anterior mesendoderm, and midline progenitors. Conditional inactivation of Lhx1 disrupts anterior definitive endoderm development and impedes node and midline morphogenesis in part due to severe disturbances in visceral endoderm displacement. Transcriptional profiling and ChIP-seq (chromatin immunoprecipitation [ChIP] followed by high-throughput sequencing) experiments identified Lhx1 target genes, including numerous anterior definitive endoderm markers and components of the Wnt signaling pathway. Interestingly, Lhx1-binding sites were enriched at enhancers, including the Nodal-proximal epiblast enhancer element and enhancer regions controlling Otx2 and Foxa2 expression. Moreover, in proteomic experiments, we characterized a complex comprised of Lhx1, Otx2, and Foxa2 as well as the chromatin-looping protein Ldb1. These partnerships cooperatively regulate development of the anterior mesendoderm, node, and midline cell populations responsible for establishment of the left–right body axis and head formation.
format Online
Article
Text
id pubmed-4617976
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher Cold Spring Harbor Laboratory Press
record_format MEDLINE/PubMed
spelling pubmed-46179762015-10-28 Lhx1 functions together with Otx2, Foxa2, and Ldb1 to govern anterior mesendoderm, node, and midline development Costello, Ita Nowotschin, Sonja Sun, Xin Mould, Arne W. Hadjantonakis, Anna-Katerina Bikoff, Elizabeth K. Robertson, Elizabeth J. Genes Dev Research Paper Gene regulatory networks controlling functional activities of spatially and temporally distinct endodermal cell populations in the early mouse embryo remain ill defined. The T-box transcription factor Eomes, acting downstream from Nodal/Smad signals, directly activates the LIM domain homeobox transcription factor Lhx1 in the visceral endoderm. Here we demonstrate Smad4/Eomes-dependent Lhx1 expression in the epiblast marks the entire definitive endoderm lineage, the anterior mesendoderm, and midline progenitors. Conditional inactivation of Lhx1 disrupts anterior definitive endoderm development and impedes node and midline morphogenesis in part due to severe disturbances in visceral endoderm displacement. Transcriptional profiling and ChIP-seq (chromatin immunoprecipitation [ChIP] followed by high-throughput sequencing) experiments identified Lhx1 target genes, including numerous anterior definitive endoderm markers and components of the Wnt signaling pathway. Interestingly, Lhx1-binding sites were enriched at enhancers, including the Nodal-proximal epiblast enhancer element and enhancer regions controlling Otx2 and Foxa2 expression. Moreover, in proteomic experiments, we characterized a complex comprised of Lhx1, Otx2, and Foxa2 as well as the chromatin-looping protein Ldb1. These partnerships cooperatively regulate development of the anterior mesendoderm, node, and midline cell populations responsible for establishment of the left–right body axis and head formation. Cold Spring Harbor Laboratory Press 2015-10-15 /pmc/articles/PMC4617976/ /pubmed/26494787 http://dx.doi.org/10.1101/gad.268979.115 Text en © 2015 Costello et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by/4.0/ This article, published in Genes & Development, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
spellingShingle Research Paper
Costello, Ita
Nowotschin, Sonja
Sun, Xin
Mould, Arne W.
Hadjantonakis, Anna-Katerina
Bikoff, Elizabeth K.
Robertson, Elizabeth J.
Lhx1 functions together with Otx2, Foxa2, and Ldb1 to govern anterior mesendoderm, node, and midline development
title Lhx1 functions together with Otx2, Foxa2, and Ldb1 to govern anterior mesendoderm, node, and midline development
title_full Lhx1 functions together with Otx2, Foxa2, and Ldb1 to govern anterior mesendoderm, node, and midline development
title_fullStr Lhx1 functions together with Otx2, Foxa2, and Ldb1 to govern anterior mesendoderm, node, and midline development
title_full_unstemmed Lhx1 functions together with Otx2, Foxa2, and Ldb1 to govern anterior mesendoderm, node, and midline development
title_short Lhx1 functions together with Otx2, Foxa2, and Ldb1 to govern anterior mesendoderm, node, and midline development
title_sort lhx1 functions together with otx2, foxa2, and ldb1 to govern anterior mesendoderm, node, and midline development
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4617976/
https://www.ncbi.nlm.nih.gov/pubmed/26494787
http://dx.doi.org/10.1101/gad.268979.115
work_keys_str_mv AT costelloita lhx1functionstogetherwithotx2foxa2andldb1togovernanteriormesendodermnodeandmidlinedevelopment
AT nowotschinsonja lhx1functionstogetherwithotx2foxa2andldb1togovernanteriormesendodermnodeandmidlinedevelopment
AT sunxin lhx1functionstogetherwithotx2foxa2andldb1togovernanteriormesendodermnodeandmidlinedevelopment
AT mouldarnew lhx1functionstogetherwithotx2foxa2andldb1togovernanteriormesendodermnodeandmidlinedevelopment
AT hadjantonakisannakaterina lhx1functionstogetherwithotx2foxa2andldb1togovernanteriormesendodermnodeandmidlinedevelopment
AT bikoffelizabethk lhx1functionstogetherwithotx2foxa2andldb1togovernanteriormesendodermnodeandmidlinedevelopment
AT robertsonelizabethj lhx1functionstogetherwithotx2foxa2andldb1togovernanteriormesendodermnodeandmidlinedevelopment