ZFIN ID: ZDB-PUB-150723-5
Wnt signaling and tbx16 form a bistable switch to commit bipotential progenitors to mesoderm
Bouldin, C.M., Manning, A.J., Peng, Y.H., Farr, G.H., Hung, K.L., Dong, A., Kimelman, D.
Date: 2015
Source: Development (Cambridge, England)   142: 2499-507 (Journal)
Registered Authors: Farr III, G. Hank, Kimelman, David
Keywords: Bipotential, Neuromesodermal, Somitogenesis, Spadetail, Tbx16, Wnt
MeSH Terms:
  • Animals
  • Body Patterning
  • Cell Differentiation
  • Cell Lineage
  • Cell Movement
  • Gene Expression Regulation, Developmental*
  • Heat-Shock Proteins/metabolism
  • In Situ Hybridization
  • Mesoderm/metabolism*
  • Mice
  • Microscopy, Fluorescence
  • Muscles/embryology
  • Muscles/metabolism
  • Neurons/metabolism
  • Oligonucleotides/chemistry
  • Promoter Regions, Genetic
  • Stem Cells/cytology
  • T-Box Domain Proteins/metabolism*
  • Transgenes
  • Wnt Signaling Pathway*
  • Wnt3A Protein/metabolism
  • Zebrafish
  • Zebrafish Proteins/metabolism*
PubMed: 26062939 Full text @ Development
Anterior to posterior growth of the vertebrate body is fueled by a posteriorly located population of bipotential neuro-mesodermal progenitor cells. These progenitors have a limited rate of proliferation and their maintenance is crucial for completion of the anterior-posterior axis. How they leave the progenitor state and commit to differentiation is largely unknown, in part because widespread modulation of factors essential for this process causes organism-wide effects. Using a novel assay, we show that zebrafish Tbx16 (Spadetail) is capable of advancing mesodermal differentiation cell-autonomously. Tbx16 locks cells into the mesodermal state by not only activating downstream mesodermal genes, but also by repressing bipotential progenitor genes, in part through a direct repression of sox2. We demonstrate that tbx16 is activated as cells move from an intermediate Wnt environment to a high Wnt environment, and show that Wnt signaling activates the tbx16 promoter. Importantly, high-level Wnt signaling is able to accelerate mesodermal differentiation cell-autonomously, just as we observe with Tbx16. Finally, because our assay for mesodermal commitment is quantitative we are able to show that the acceleration of mesodermal differentiation is surprisingly incomplete, implicating a potential separation of cell movement and differentiation during this process. Together, our data suggest a model in which high levels of Wnt signaling induce a transition to mesoderm by directly activating tbx16, which in turn acts to irreversibly flip a bistable switch, leading to maintenance of the mesodermal fate and repression of the bipotential progenitor state, even as cells leave the initial high-Wnt environment.