PUBLICATION

Canonical Wnt5b Signaling Directs Outlying Nkx2.5+ Mesoderm into Pacemaker Cardiomyocytes

Authors
Ren, J., Han, P., Ma, X., Farah, E.N., Bloomekatz, J., Zeng, X.I., Zhang, R., Swim, M.M., Witty, A.D., Knight, H.G., Deshpande, R., Xu, W., Yelon, D., Chen, S., Chi, N.C.
ID
ZDB-PUB-190814-2
Date
2019
Source
Developmental Cell   50(6): 729-743.e5 (Journal)
Registered Authors
Bloomekatz, Joshua, Chi, Neil C., Han, Peidong, Yelon, Deborah, Zeng, Sean
Keywords
3D bioprinting, Wnt5b, canonical Wnt signaling, differentiation, human pluripotent stem cells, pacemaker cardiomyocytes, zebrafish
MeSH Terms
  • Zebrafish
  • Wnt Proteins/metabolism*
  • Bioprinting
  • Loss of Function Mutation/genetics
  • Gene Expression Regulation, Developmental
  • Animals
  • Pluripotent Stem Cells/cytology
  • Pluripotent Stem Cells/metabolism
  • Humans
  • Myocytes, Cardiac/cytology
  • Myocytes, Cardiac/metabolism*
  • Homeobox Protein Nkx-2.5/metabolism*
  • Mesoderm/metabolism*
  • Stem Cells/metabolism
  • Models, Cardiovascular
  • Signal Transduction*
  • Base Sequence
  • Cell Differentiation
(all 18)
PubMed
31402282 Full text @ Dev. Cell
Abstract
Pacemaker cardiomyocytes that create the sinoatrial node are essential for the initiation and maintenance of proper heart rhythm. However, illuminating developmental cues that direct their differentiation has remained particularly challenging due to the unclear cellular origins of these specialized cardiomyocytes. By discovering the origins of pacemaker cardiomyocytes, we reveal an evolutionarily conserved Wnt signaling mechanism that coordinates gene regulatory changes directing mesoderm cell fate decisions, which lead to the differentiation of pacemaker cardiomyocytes. We show that in zebrafish, pacemaker cardiomyocytes derive from a subset of Nkx2.5+ mesoderm that responds to canonical Wnt5b signaling to initiate the cardiac pacemaker program, including activation of pacemaker cell differentiation transcription factors Isl1 and Tbx18 and silencing of Nkx2.5. Moreover, applying these developmental findings to human pluripotent stem cells (hPSCs) notably results in the creation of hPSC-pacemaker cardiomyocytes, which successfully pace three-dimensional bioprinted hPSC-cardiomyocytes, thus providing potential strategies for biological cardiac pacemaker therapy.
Genes / Markers
Marker Marker Type Name
apcGENEAPC regulator of WNT signaling pathway
hcn4GENEhyperpolarization activated cyclic nucleotide-gated potassium channel 4
nkx2.5GENENK2 homeobox 5
shox2GENEshox homeobox 2
tbx18GENET-box transcription factor 18
tcf7l1aGENEtranscription factor 7 like 1a
wnt5bGENEwingless-type MMTV integration site family, member 5b
1 - 7 of 7
Show
Figures
Figure Gallery (1 images)
Show all Figures
Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
co19TgTransgenic Insertion
    fb7TgTransgenic Insertion
      fb9TgTransgenic Insertion
        fcu1TgTransgenic Insertion
          ia5TgTransgenic Insertion
            s878TgTransgenic Insertion
              s958TgTransgenic Insertion
                sd12TgTransgenic Insertion
                  sd58
                    Point Mutation
                    ta98
                      Point Mutation
                      1 - 10 of 14
                      Show
                      Human Disease / Model
                      No data available
                      Sequence Targeting Reagents
                      No data available
                      Fish
                      Antibodies
                      Name Type Antigen Genes Isotypes Host Organism
                      Ab1-nkx2.5monoclonal
                        IgGRabbit
                        Ab1-shox2monoclonalIgG2aMouse
                        Ab2-ctnnbmonoclonalIgG1Mouse
                        Ab2-islmonoclonalIgG2bMouse
                        Ab2-isl1polyclonal
                          Rabbit
                          Ab3-nkx2.5polyclonal
                            IgGRabbit
                            Ab4-h3polyclonal
                              IgGRabbit
                              Ab-MF20monoclonal
                                IgG2bMouse
                                1 - 8 of 8
                                Show
                                Orthology
                                No data available
                                Engineered Foreign Genes
                                Marker Marker Type Name
                                CeruleanEFGCerulean
                                EGFPEFGEGFP
                                GAL4EFGGAL4
                                GCaMPEFGGCaMP
                                GFPEFGGFP
                                KaedeEFGKaede
                                mCherryEFGmCherry
                                ZsYellowEFGZsYellow
                                1 - 8 of 8
                                Show
                                Mapping
                                No data available