Complementary functions of Otx2 and Cripto in initial patterning of mouse epiblast

Dev Biol. 2001 Jul 1;235(1):12-32. doi: 10.1006/dbio.2001.0289.


The development of the mammalian antero-posterior (A-P) axis is proposed to be established by distinct anterior and posterior signaling centers, anterior visceral endoderm and primitive streak, respectively. Knock-out studies in mice have shown that Otx2 and Cripto have crucial roles in the generation and/or functions of these anterior and posterior centers, respectively. In both Otx2 and Cripto single mutants, the initial formation of the A-P axis takes place in a proximal-distal (P-D) orientation, but subsequent axis rotation fails to occur. To examine the developmental consequences of the lack of these two genes, we have analyzed the Otx2(-/-);Cripto(-/-) double homozygous mutant phenotype. In the double mutants, the expression of the A-P axis markers Cer-l, Lim1, and Wnt3 was not induced, while expression of Fgf8 and T was expanded throughout the epiblast, indicating that the double mutants could not form the A-P axis even in its initial P-D orientation. In addition, the double mutants displayed defects in differentiation of the visceral endoderm overlying the epiblast, as well as in the extraembryonic ectoderm. Furthermore, differentiation of neuroectoderm was accelerated as judged by the reduction of Oct4 expression and emergence of Sox1 and Gbx2 expression in the double mutant epiblast. The resulting ectoderm only displayed characteristics of anterior hindbrain, implicating it as a ground state in the mammalian body plan. Our results indicate that complementary functions of Otx2 and Cripto are essential for initial patterning of the A-P axis in the mouse embryo.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Base Sequence
  • Body Patterning / physiology*
  • Cell Differentiation
  • DNA Primers
  • Epidermal Growth Factor*
  • Homeodomain Proteins*
  • Homozygote
  • In Situ Hybridization
  • Membrane Glycoproteins*
  • Mice
  • Mutation
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / physiology*
  • Otx Transcription Factors
  • Reverse Transcriptase Polymerase Chain Reaction
  • Trans-Activators / genetics
  • Trans-Activators / physiology*


  • DNA Primers
  • Homeodomain Proteins
  • Membrane Glycoproteins
  • Neoplasm Proteins
  • Nerve Tissue Proteins
  • Otx Transcription Factors
  • Otx2 protein, mouse
  • Tdgf1 protein, mouse
  • Trans-Activators
  • Epidermal Growth Factor