A molecular pathway leading to endoderm formation in zebrafish

Curr Biol. 1999 Oct 21;9(20):1147-57. doi: 10.1016/S0960-9822(00)80016-0.


Background: Several potentially important regulators of vertebrate endoderm development have been identified, including Activin-related growth factors and their receptors; transcriptional regulators encoded by the genes Mixer, Xsox17, and HNF3beta; zebrafish One-eyed pinhead (Oep), a member of the Cripto/FRL-1/Cryptic family of epidermal growth factor related proteins (EGF-CFC); and the product of the zebrafish locus casanova, which plays an essential cell-autonomous role in endoderm formation.

Results: Using overexpression studies and the analysis of different zebrafish mutants, we have assembled a molecular pathway that leads to endoderm formation. We report that a zebrafish Sox17 homologue is expressed during gastrulation exclusively in the endoderm and that casanova mutants lack all sox17 expression. Overexpression of mixer induces ectopic sox17-expressing cells in wild-type embryos and promotes endoderm formation in oep mutants, but does not rescue sox17 expression or endoderm formation in casanova mutants. Overexpression of a constitutively active form of the type I transforming growth factor beta (TGF-beta) receptor TARAM-A also promotes sox17 expression in wild-type and oep mutant embryos, but not in casanova mutants. We also show that the Nodal-related molecules Cyclops and Squint and the transmembrane protein Oep are essential for normal mixer expression.

Conclusions: The data indicate that the following pathway leads to zebrafish endoderm formation: Cyclops and Squint activate receptors such as TARAM-A; Oep also appears to act upstream of such receptors; signals transduced by these receptors lead to the expression of mixer, Mixer then acts through casanova to promote the expression of sox17 and differentiation of the endoderm.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • DNA-Binding Proteins*
  • Endoderm / cytology
  • Endoderm / metabolism
  • Female
  • Gene Expression Regulation, Developmental
  • High Mobility Group Proteins*
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Molecular Sequence Data
  • Mutation
  • Nodal Signaling Ligands
  • Protein-Serine-Threonine Kinases*
  • Proteins / genetics
  • Receptors, Growth Factor / genetics
  • Receptors, Transforming Growth Factor beta*
  • SOXF Transcription Factors
  • Signal Transduction
  • Transcription Factors*
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism
  • Zebrafish / embryology*
  • Zebrafish / genetics*
  • Zebrafish / metabolism
  • Zebrafish Proteins*


  • DNA-Binding Proteins
  • High Mobility Group Proteins
  • Intracellular Signaling Peptides and Proteins
  • Nodal Signaling Ligands
  • Proteins
  • Receptors, Growth Factor
  • Receptors, Transforming Growth Factor beta
  • SOXF Transcription Factors
  • Transcription Factors
  • Transforming Growth Factor beta
  • Zebrafish Proteins
  • ndr1 protein, zebrafish
  • ndr2 protein, zebrafish
  • sox17 protein, zebrafish
  • Protein-Serine-Threonine Kinases

Associated data

  • GENBANK/AF168614