Role and regulation of Nodal signaling during zebrafish development

Nodal, a member of the TGF? family of ligands, has been implicated in many events during vertebrate development, such as germ layer formation, axis determination, and neural patterning. Genetic evidence in mouse and zebrafish suggests that Nodal transduces signals via Ser/Thr kinase receptors and the transcription factor Smad2. Using cellular and genetic approaches, I have examined the role and regulation of Nodal signaling during zebrafish development. Evidence is presented here that the permissive EGF-CFC protein One-eyed pinhead acts as an essential extracellular cofactor for Nodal signaling. My results indicate that One eyed pinhead is required for all processes that have been reported to involve Nodal, including germ layer formation, gastrulation, positioning of the anterior-posterior axis, and left-right determination. In addition, I found that the divergent TGF? ligand Antivin acts as an extracellular feedback inhibitor of Nodal signaling. Together, these results reveal a sophisticated system to regulate Nodal signaling during development. Nodal signaling is dependent on the cofactor Oep, and it is rendered transient by the feedback inhibitor Antivin. Finally, I have uncovered a role for differential Nodal signaling in anterior-posterior patterning of Spemann's organizer, suggesting that Nodal may act as a morphogen.