A molecular pathway leading to endoderm formation in zebrafish.
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.
Alexander
J
J
Department of Biochemistry and Biophysics, Programs in Developmental Biology and Human Genetics, University of California at San Francisco, San Francisco, California 94143-0448, USA.
Stainier
D Y
DY
D000595:Amino Acid Sequence; D000818:Animals; D004268:DNA-Binding Proteins; D004707:Endoderm / Q000166:cytology / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006609:High Mobility Group Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D055456:Nodal Signaling Ligands; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000235:genetics; D017978:Receptors, Growth Factor / Q000235:genetics; D018125:Receptors, Transforming Growth Factor beta; D055760:SOXF Transcription Factors; D015398:Signal Transduction; D014157:Transcription Factors; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics* / Q000378:metabolism; D029961:Zebrafish Proteins
D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D047908:Intracellular Signaling Peptides and Proteins; D055456:Nodal Signaling Ligands; D011506:Proteins; D017978:Receptors, Growth Factor; D018125:Receptors, Transforming Growth Factor beta; D055760:SOXF Transcription Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D029961:Zebrafish Proteins; C485171:ndr1 protein, zebrafish; C512832:ndr2 protein, zebrafish; C491603:sox17 protein, zebrafish; D017346:Protein Serine-Threonine Kinases