Head formation: OTX2 regulates <i>Dkk1</i> and <i>Lhx1</i> activity in the anterior mesendoderm

Ip, Chi Kin; Fossat, Nicolas; Jones, Vanessa; Lamonerie, Thomas; Tam, Patrick

doi:10.1242/dev.114900

Cited by 26 publications

(34 citation statements)

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“…OTX2 can directly regulate Cer1 and Gsc in Xenopus (Sudou et al, 2012;Yasuoka et al, 2014) and Hesx1 in chicken (Spieler et al, 2004). Lhx1 is also a target of OTX2 and its expression in the AME is regulated by OTX2 (Ip et al, 2014). Together, our findings reveal an upstream function of LHX1, which may act in conjunction with OTX2, in regulating the expression of genes that encode secreted molecules (e.g.…”

Section: Discussionmentioning

confidence: 60%

“…In the AME, LHX1 function intersects with the WNT pathway via transcriptional control of modulators of WNT signalling activity. LHX1 binds to a regulatory region of Dkk1 that also interacts with another transcription factor, OTX2 (Kimura- Yoshida et al, 2005;Ip et al, 2014), and OTX2 and LHX1 are part of the same activator complex (Nakano et al, 2000;Yasuoka et al, 2014). OTX2 can directly regulate Cer1 and Gsc in Xenopus (Sudou et al, 2012;Yasuoka et al, 2014) and Hesx1 in chicken (Spieler et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…Expression of the lacZ reporter in tamoxifen-treated Foxa2 +/mcm ;Rosa26 +/R26R embryos showed that MerCreMer was activated widely in the endoderm layer of the embryo, which encompassed the Lhx1-expressing AME tissues (Fig. 4A) (Park et al, 2008;Ip et al, 2014 (Fig. 4B).…”

Section: Loss Of Lhx1 Disrupts the Formation Of Anterior Midline Tissuesmentioning

confidence: 99%

“…A conserved region of the mouse Dkk1 locus, referred to as H1, has been shown to be necessary for the control of Dkk1 expression (Kimura- Yoshida et al, 2005). This region is bound by another homeobox transcription factor, OTX2 (Kimura- Yoshida et al, 2005;Ip et al, 2014), which can directly interact with LHX1 to activate target genes involved in head formation (Nakano et al, 2000;Yasuoka et al, 2014). We analysed the H1 region of Dkk1 and found two putative LHX1 recognition motifs, one localised at the distal (dH1) end and one at the proximal end ( Fig.…”

Section: Loss Of Lhx1 Disrupts the Formation Of Anterior Midline Tissuesmentioning

confidence: 99%

“…P19 cells were transfected with pGL3-promoter (empty or containing a genomic region), a pRL vector and different combinations of mock plasmid, pLhx1-HA, pLhx1Δ-HA, pLdb1 and/or pSsbp3 in equimolar quantity (see supplementary Materials and Methods for details). The luciferase assay was performed as described previously (Ip et al, 2014).…”

Section: Molecular Cloning and Luciferase Assaymentioning

confidence: 99%

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Context-specific function of the LIM homeobox 1 transcription factor in head formation of the mouse embryo

Fossat

Jones

et al. 2015

Development

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Lhx1 encodes a LIM homeobox transcription factor that is expressed in the primitive streak, mesoderm and anterior mesendoderm of the mouse embryo. Using a conditional Lhx1 flox mutation and three different Cre deleters, we demonstrated that LHX1 is required in the anterior mesendoderm, but not in the mesoderm, for formation of the head. LHX1 enables the morphogenetic movement of cells that accompanies the formation of the anterior mesendoderm, in part through regulation of Pcdh7 expression. LHX1 also regulates, in the anterior mesendoderm, the transcription of genes encoding negative regulators of WNT signalling, such as Dkk1, Hesx1, Cer1 and Gsc. Embryos carrying mutations in Pcdh7, generated using CRISPRCas9 technology, and embryos without Lhx1 function specifically in the anterior mesendoderm displayed head defects that partially phenocopied the truncation defects of Lhx1-null mutants. Therefore, disruption of Lhx1-dependent movement of the anterior mesendoderm cells and failure to modulate WNT signalling both resulted in the truncation of head structures. Compound mutants of Lhx1, Dkk1 and Ctnnb1 show an enhanced head truncation phenotype, pointing to a functional link between LHX1 transcriptional activity and the regulation of WNT signalling. Collectively, these results provide comprehensive insight into the context-specific function of LHX1 in head formation: LHX1 enables the formation of the anterior mesendoderm that is instrumental for mediating the inductive interaction with the anterior neuroectoderm and LHX1 also regulates the expression of factors in the signalling cascade that modulate the level of WNT activity.

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Section: Loss Of Lhx1 Disrupts the Formation Of Anterior Midline Tissuesmentioning

confidence: 99%

Section: Loss Of Lhx1 Disrupts the Formation Of Anterior Midline Tissuesmentioning

confidence: 99%

Section: Molecular Cloning and Luciferase Assaymentioning

confidence: 99%

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Context-specific function of the LIM homeobox 1 transcription factor in head formation of the mouse embryo

Fossat

Jones

et al. 2015

Development

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Conserved and divergent expression patterns of markers of axial development in eutherian mammals

Yoshida¹,

Kajikawa²,

Kurokawa³

et al. 2015

Developmental Dynamics

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Background: Mouse embryos are cup shaped, but most nonrodent eutherian embryos are disk shaped. Extraembryonic ectoderm (ExEc), which may have essential roles in anterior-posterior (A-P) axis formation in mouse embryos, does not develop in many eutherian embryos. To assess A-P axis formation in eutherians, comparative analyses were made on rabbit, porcine, and Suncus embryos. Results: All embryos examined expressed Nodal initially throughout epiblast and visceral endoderm; its expression became restricted to the posterior region before gastrulation. Anterior visceral endoderm (AVE) genes were expressed in Otx2-positive visceral endoderm, with Dkk1 expression being most anterior. The mouse pattern of AVE formation was conserved in rabbit embryos, but had diverged in porcine and Suncus embryos. No structure that was molecularly equivalent to Bmp-positive ExEc, existed in rabbit or pig embryos. In Suncus embryos, A-P axis was determined at prehatching stage, and these embryos attached to uterine wall at future posterior side. Conclusions: Nodal, but not Bmp, functions in epiblast and visceral endoderm development may be conserved in eutherians. AVE functions may also be conserved, but the pattern of its formation has diverged among eutherians. Roles of BMP and NODAL gradients in AVE formation seem to have been established in a subset of rodents. Developmental Dynamics 245:67-86, 2016. V C 2015 Wiley Periodicals, Inc.

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A gene regulatory network anchored by LIM homeobox 1 for embryonic head development

Sibbritt

Khoo

et al. 2018

Genesis

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Development of the embryonic head is driven by the activity of gene regulatory networks of transcription factors. LHX1 is a homeobox transcription factor that plays an essential role in the formation of the embryonic head. The loss of LHX1 function results in anterior truncation of the embryo caused by the disruption of morphogenetic movement of tissue precursors and the dysregulation of WNT signaling activity. Profiling the gene expression pattern in the Lhx1 mutant embryo revealed that tissues in anterior germ layers acquire posterior tissue characteristics, suggesting LHX1 activity is required for the allocation and patterning of head precursor tissues. Here, we used LHX1 as an entry point to delineate its transcriptional targets and interactors and construct a LHX1-anchored gene regulatory network. Using a gain-of-function approach, we identified genes that immediately respond to Lhx1 activation. Meta-analysis of the datasets of LHX1-responsive genes and genes expressed in the anterior tissues of mouse embryos at head-fold stage, in conjunction with published Xenopus embryonic LHX1 (Xlim1) ChIP-seq data, has pinpointed the putative transcriptional targets of LHX1 and an array of genetic determinants functioning together in the formation of the mouse embryonic head.

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Head formation: OTX2 regulates Dkk1 and Lhx1 activity in the anterior mesendoderm

Cited by 26 publications

References 50 publications

Context-specific function of the LIM homeobox 1 transcription factor in head formation of the mouse embryo

Context-specific function of the LIM homeobox 1 transcription factor in head formation of the mouse embryo

Conserved and divergent expression patterns of markers of axial development in eutherian mammals

A gene regulatory network anchored by LIM homeobox 1 for embryonic head development

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