Sequential roles for Otx2 in visceral endoderm and neuroectoderm for forebrain and midbrain induction and specification.
The homeobox gene Otx2 is a mouse cognate of the Drosophila orthodenticle gene, which is required for development of the brain, rostral to rhombomere three. We have investigated the mechanisms involved in this neural function and specifically the requirement for Otx2 in the visceral endoderm and the neuroectoderm using chimeric analysis in mice and explant recombination assay. Analyses of chimeric embryos composed of more than 90% of Otx2-/- ES cells identified an essential function for Otx2 in the visceral endoderm for induction of the forebrain and midbrain. The chimeric studies also demonstrated that an anterior neural plate can form without expressing Otx2. However, in the absence of Otx2, expression of important regulatory genes, such as Hesx1/Rpx, Six3, Pax2, Wnt1 and En, fail to be initiated or maintained in the neural plate. Using explant-recombination assay, we could further demonstrate that Otx2 is required in the neuroectodem for expression of En. Altogether, these results demonstrate that Otx2 is first required in the visceral endoderm for the induction, and subsequently in the neuroectoderm for the specification of forebrain and midbrain territories.
Rhinn
M
M
Institut de Genetique et de Biologie Moleculaire et Cellulaire, CNRS/INSERM/Universite Louis Pasteur, Strasbourg, France.
Dierich
A
A
Shawlot
W
W
Behringer
R R
RR
Le Meur
M
M
Ang
S L
SL
D000818:Animals; D002352:Carrier Proteins; D002460:Cell Line; D002678:Chimera / Q000235:genetics; D004330:Drosophila / Q000196:embryology / Q000235:genetics; D004475:Ectoderm / Q000378:metabolism; D004627:Embryonic Induction / Q000235:genetics; D004707:Endoderm / Q000378:metabolism; D005260:Female; D038681:Follistatin; D018507:Gene Expression Regulation, Developmental; D005801:Genes, Homeobox; D017344:Genes, Insect; D006023:Glycoproteins / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics*; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D008636:Mesencephalon / Q000002:abnormalities / Q000196:embryology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009419:Nerve Tissue Proteins / Q000235:genetics*; D051857:Otx Transcription Factors; D011247:Pregnancy; D016548:Prosencephalon / Q000002:abnormalities / Q000196:embryology* / Q000378:metabolism*; D011506:Proteins / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics*; D000099176:Noggin Protein
D002352:Carrier Proteins; D038681:Follistatin; D006023:Glycoproteins; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D051857:Otx Transcription Factors; D011506:Proteins; D015534:Trans-Activators; D000099176:Noggin Protein; C497660:Otx2 protein, mouse; C054234:chordin