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.
authors.affiliation: Embryology Unit, Children's Medical Research Institute, Westmead, New South Wales 2145, Australia Discipline of Medicine, Sydney Medical School, University of Sydney, Sydney, New South Wales 2006, Australia nfossat@cmri.org.au.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Fossat
authors.affiliation: Embryology Unit, Children's Medical Research Institute, Westmead, New South Wales 2145, Australia Discipline of Medicine, Sydney Medical School, University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Chi Kin
authors.initials: CK
authors.lastname: Ip
authors.affiliation: Embryology Unit, Children's Medical Research Institute, Westmead, New South Wales 2145, Australia.
authors.forename: Vanessa J
authors.initials: VJ
authors.lastname: Jones
authors.affiliation: Embryology Unit, Children's Medical Research Institute, Westmead, New South Wales 2145, Australia.
authors.forename: Joshua B
authors.initials: JB
authors.lastname: Studdert
authors.affiliation: Embryology Unit, Children's Medical Research Institute, Westmead, New South Wales 2145, Australia.
authors.forename: Poh-Lynn
authors.initials: PL
authors.lastname: Khoo
authors.affiliation: Embryology Unit, Children's Medical Research Institute, Westmead, New South Wales 2145, Australia.
authors.forename: Samara L
authors.initials: SL
authors.lastname: Lewis
authors.affiliation: Embryology Unit, Children's Medical Research Institute, Westmead, New South Wales 2145, Australia.
authors.forename: Melinda
authors.initials: M
authors.lastname: Power
authors.affiliation: Embryology Unit, Children's Medical Research Institute, Westmead, New South Wales 2145, Australia.
authors.forename: Karin
authors.initials: K
authors.lastname: Tourle
authors.affiliation: Embryology Unit, Children's Medical Research Institute, Westmead, New South Wales 2145, Australia Discipline of Medicine, Sydney Medical School, University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: David A F
authors.initials: DA
authors.lastname: Loebel
authors.affiliation: Department of Genetics, MD Anderson Cancer Center, University of Texas, Houston, TX 77005, USA.
authors.forename: Kin Ming
authors.initials: KM
authors.lastname: Kwan
authors.affiliation: Department of Genetics, MD Anderson Cancer Center, University of Texas, Houston, TX 77005, USA.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Behringer
authors.affiliation: Embryology Unit, Children's Medical Research Institute, Westmead, New South Wales 2145, Australia Discipline of Medicine, Sydney Medical School, University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Patrick P L
authors.initials: PP
authors.lastname: Tam
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism*; D004707:Endoderm / Q000166:cytology / Q000378:metabolism; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D005855:Germ Layers / Q000166:cytology / Q000378:metabolism; D006257:Head / Q000196:embryology*; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D018345:Mice, Knockout; D008954:Models, Biological; D009154:Mutation; D010641:Phenotype; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D015820:Cadherins; D060850:LIM-Homeodomain Proteins; C499523:Lhx1 protein, mouse; D014157:Transcription Factors; D051153:Wnt Proteins
keywords: Anterior mesendoderm; CRISPR; Head formation; LHX1; Protocadherin; Transcription factor; WNT signalling