title: Cell fate decisions within the mouse organizer are governed by graded Nodal signals.
abstract: It is well known that cell fate decisions in the mouse organizer region during gastrulation ultimately govern gut formation and patterning, left-right axis determination, and development of the central nervous system. Previous studies suggest that signaling pathways activated by Nodal, bone morphogenetic protein (BMP), and Wnt ligands coordinately regulate patterning of the streak and the formation of midline organizing tissues, but the specific contributions of these molecules within discrete cell lineages are poorly defined. Here we removed Smad2 activity in the epiblast, using a conditional inactivation strategy. Abrogation of Smad2 does not compromise primitive streak (PS) formation or gastrulation movements, but rather results in a failure to correctly specify the anterior definitive endoderm (ADE) and prechordal plate (PCP) progenitors. To selectively lower Nodal activity in the posterior epiblast, we generated a novel allele lacking the proximal epiblast enhancer (PEE) governing Nodal expression in the PS. As for conditional inactivation of Smad2, germ-line deletion of the PEE selectively disrupts development of the anterior streak. In striking contrast, the node and its midline derivatives, the notochord and floor plate, develop normally in both categories of mutant embryos. Finally, we show that removal of one copy of Smad3 in the context of a Smad2-deficient epiblast results in a failure to specify all axial midline tissues. These findings conclusively demonstrate that graded Nodal/Smad2 signals govern allocation of the axial mesendoderm precursors that selectively give rise to the ADE and PCP mesoderm.
authors.affiliation: Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: Stephane D
authors.initials: SD
authors.lastname: Vincent
authors.forename: N Ray
authors.initials: NR
authors.lastname: Dunn
authors.forename: Shigemi
authors.initials: S
authors.lastname: Hayashi
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Norris
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Robertson
mesh_terms: D000483:Alleles; D000818:Animals; D019521:Body Patterning; D002490:Central Nervous System / Q000196:embryology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004064:Digestive System / Q000196:embryology; D004475:Ectoderm / Q000502:physiology; D005314:Embryonic and Fetal Development; D004707:Endoderm / Q000502:physiology; D004742:Enhancer Elements, Genetic; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005775:Gastrula / Q000502:physiology*; D018390:Gene Targeting; D018398:Homeodomain Proteins; D008648:Mesoderm / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D055457:Nodal Protein; D020897:Organizers, Embryonic / Q000166:cytology* / Q000502:physiology; D051857:Otx Transcription Factors; D015398:Signal Transduction; D051899:Smad2 Protein; D051900:Smad3 Protein; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D019076:Transgenes
chemical_list: D004268:DNA-Binding Proteins; C496457:Fgf8 protein, mouse; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D055457:Nodal Protein; C526008:Nodal protein, mouse; D051857:Otx Transcription Factors; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors