Three groups of mouse mutants that show impaired AVE formation. Three groups of mouse mutants that show impaired AVE formation. (A) Behaviors of DVE-lineage and AVE-lineage cells are shown for the wild-type embryo, together with main signaling events. At E6.0 and E6.5, signals from the AVE (and possibly DVE) specify the nearby epiblast by inhibiting Nodal signaling and Wnt signaling. On the opposite side far from the AVE, Nodal and Wnt signaling remains active, which results in the formation of the primitive streak (light green). (B) Three groups of mouse mutants defective in AVE formation are illustrated. Yellow and orange indicate normal and abnormal epiblast, respectively. Dark and light blue indicate normal and abnormal visceral endoderm, respectively. (a) The DVE and AVE fail to form throughout E5.5 and E6.5. (b) The DVE does not form at E5.5. AVE is newly formed at the distal tip at E6.0 but fails to migrate. As a result, cells positive for Brachyury expression (which marks primitive streak-like cells) form at the proximal side of the embryo. (c) The DVE forms at the distal tip of the embryo at E5.5 but fails to migrate. Cells positive for DVE/AVE markers remain at the distal tip at E6.0 and E6.5. As a result, cells that express primitive streak markers are found at the proximal side of the embryo. AVE, anterior visceral endoderm; Bmp4, bone morphogenetic protein 4; Cripto, cryptic family 1; Dkk1, dickkopf homolog 1; DVE, dorsal visceral endoderm; Lefty1, left-right determination factor; Otx2, orthodenticle homolog 2; Rac1, RAS-related C3 botulinum substrate 1; Smad2, MAD homolog 2. Katsuyoshi Takaoka, and Hiroshi Hamada Development 2012;139:3-14 © 2012.