title: Mixer/Bon and FoxH1/Sur have overlapping and divergent roles in Nodal signaling and mesendoderm induction.
abstract: Transcription factors belonging to the FoxH1 and Mixer families are required for facets of Nodal signaling during vertebrate mesendoderm induction. Here, we analyze whether zebrafish proteins related to FoxH1 [Schmalspur (Sur)] and Mixer [Bonnie and clyde (Bon)] act within or downstream of the Nodal signaling pathway, test whether these two factors have additive or overlapping activities, and determine whether FoxH1/Sur and Mixer/Bon can account for all Nodal signaling during embryogenesis. We find that sur expression is independent of Nodal signaling and that bon is expressed in the absence of Nodal signaling but requires Nodal signaling and Sur for enhanced, maintained expression. These results and the association of FoxH1 and Mixer/Bon with phosphorylated Smad2 support a role for these factors as components of the Nodal signaling pathway. In contrast to the relatively mild defects observed in single mutants, loss of both bon and sur results in a severe phenotype characterized by absence of prechordal plate, cardiac mesoderm, endoderm and ventral neuroectoderm. Analysis of Nodal-regulated proteins reveals that Bon and Sur have both distinct and overlapping regulatory roles. Some genes are regulated by both Bon and Sur, and others by either Bon or Sur. Complete loss of Nodal signaling results in a more severe phenotype than loss of both Bon and Sur, indicating that additional Smad-associated transcription factors remain to be identified that act as components of the Nodal signaling pathway.
authors.affiliation: Developmental Genetics Program, Skirball Institute of Biomolecular Medicine, Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Prabhat S
authors.initials: PS
authors.lastname: Kunwar
authors.forename: Steven
authors.initials: S
authors.lastname: Zimmerman
authors.forename: James T
authors.initials: JT
authors.lastname: Bennett
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.forename: Malcolm
authors.initials: M
authors.lastname: Whitman
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Schier
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004627:Embryonic Induction; D051858:Forkhead Transcription Factors; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D017403:In Situ Hybridization; D008648:Mesoderm / Q000502:physiology*; D009024:Morphogenesis; D055457:Nodal Protein; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051899:Smad2 Protein; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology* / Q000378:metabolism; D029961:Zebrafish Proteins
chemical_list: D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C491117:Foxh1 protein, mouse; D018398:Homeodomain Proteins; D055457:Nodal Protein; C526008:Nodal protein, mouse; D016376:Oligonucleotides, Antisense; D051899:Smad2 Protein; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D029961:Zebrafish Proteins; C499590:mixl1 protein, zebrafish; C497786:smad2 protein, zebrafish