Otx2 is required for visceral endoderm movement and for the restriction ofposterior signals in the epiblast of the mouse embryo

Genetic and embryological experiments have demonstrated an essential role f or the visceral endoderm in the formation of the forebrain; however, the pr ecise molecular and cellular mechanisms of this requirement are poorly unde rstood. We have performed lineage tracing in combination with molecular mar ker studies to follow morphogenetic movements and cell fates before and dur ing gastrulation in embryos mutant for the homeobox gene Otx2, Our results show first, that Otx2 is not required for proliferation of the visceral end oderm, but is essential for anteriorly directed morphogenetic movement. Sec ond, molecules that are normally expressed in the anterior visceral endoder m, such as Lefty1 and Mdkk1, are not expressed in Otx2 mutants. These secre ted proteins have been reported to antagonise, respectively, the activities of Nodal and Wnt signals, which have a role in regulating primitive streak formation. The visceral endoderm defects of the Otx2 mutants are associate d with abnormal expression of primitive streak markers in the epiblast, sug gesting that anterior epiblast cells acquire primitive streak characteristi cs. Taken together, our data support a model whereby Otx2 functions in the anterior visceral endoderm to influence the ability of the adjacent epiblas t cells to differentiate into anterior neurectoderm, indirectly, by prevent ing them from coming under the influence of posterior signals that regulate primitive streak formation.