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

Nicolas Fossat, Chi Kin Ip, Vanessa J. Jones, Joshua B. Studdert, Poh Lynn Khoo, Samara L. Lewis, Melinda Power, Karin Tourle, David A.F. Loebel, Kin Ming Kwan, Richard R. Behringer, Patrick P.L. Tam

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Abstract

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 CRISPR-Cas9 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.

Original languageEnglish
Pages (from-to)2069-2079
Number of pages11
JournalDevelopment (Cambridge)
Volume142
Issue number11
DOIs
Publication statusPublished - 2015
Externally publishedYes

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Homeobox Genes
Transcription Factors
Embryonic Structures
Head
Mesoderm
Clustered Regularly Interspaced Short Palindromic Repeats
Primitive Streak
Neural Plate
Mutation
Cell Movement
Technology
Phenotype
Genes

Cite this

Fossat, N., Ip, C. K., Jones, V. J., Studdert, J. B., Khoo, P. L., Lewis, S. L., ... Tam, P. P. L. (2015). Context-specific function of the LIM homeobox 1 transcription factor in head formation of the mouse embryo. Development (Cambridge), 142(11), 2069-2079. https://doi.org/10.1242/dev.120907
Fossat, Nicolas ; Ip, Chi Kin ; Jones, Vanessa J. ; Studdert, Joshua B. ; Khoo, Poh Lynn ; Lewis, Samara L. ; Power, Melinda ; Tourle, Karin ; Loebel, David A.F. ; Kwan, Kin Ming ; Behringer, Richard R. ; Tam, Patrick P.L. / Context-specific function of the LIM homeobox 1 transcription factor in head formation of the mouse embryo. In: Development (Cambridge). 2015 ; Vol. 142, No. 11. pp. 2069-2079.
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title = "Context-specific function of the LIM homeobox 1 transcription factor in head formation of the mouse embryo",
abstract = "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 CRISPR-Cas9 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.",
author = "Nicolas Fossat and Ip, {Chi Kin} and Jones, {Vanessa J.} and Studdert, {Joshua B.} and Khoo, {Poh Lynn} and Lewis, {Samara L.} and Melinda Power and Karin Tourle and Loebel, {David A.F.} and Kwan, {Kin Ming} and Behringer, {Richard R.} and Tam, {Patrick P.L.}",
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language = "English",
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Fossat, N, Ip, CK, Jones, VJ, Studdert, JB, Khoo, PL, Lewis, SL, Power, M, Tourle, K, Loebel, DAF, Kwan, KM, Behringer, RR & Tam, PPL 2015, 'Context-specific function of the LIM homeobox 1 transcription factor in head formation of the mouse embryo' Development (Cambridge), vol. 142, no. 11, pp. 2069-2079. https://doi.org/10.1242/dev.120907

Context-specific function of the LIM homeobox 1 transcription factor in head formation of the mouse embryo. / Fossat, Nicolas; Ip, Chi Kin; Jones, Vanessa J.; Studdert, Joshua B.; Khoo, Poh Lynn; Lewis, Samara L.; Power, Melinda; Tourle, Karin; Loebel, David A.F.; Kwan, Kin Ming; Behringer, Richard R.; Tam, Patrick P.L.

In: Development (Cambridge), Vol. 142, No. 11, 2015, p. 2069-2079.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Context-specific function of the LIM homeobox 1 transcription factor in head formation of the mouse embryo

AU - Fossat, Nicolas

AU - Ip, Chi Kin

AU - Jones, Vanessa J.

AU - Studdert, Joshua B.

AU - Khoo, Poh Lynn

AU - Lewis, Samara L.

AU - Power, Melinda

AU - Tourle, Karin

AU - Loebel, David A.F.

AU - Kwan, Kin Ming

AU - Behringer, Richard R.

AU - Tam, Patrick P.L.

PY - 2015

Y1 - 2015

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AB - 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 CRISPR-Cas9 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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U2 - 10.1242/dev.120907

DO - 10.1242/dev.120907

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SN - 0950-1991

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