Wnt4 enhances murine hematopoietic progenitor cell expansion through a planar cell polarity-like pathway

PLoS One. 2011 Apr 26;6(4):e19279. doi: 10.1371/journal.pone.0019279.


Background: While the role of canonical (β-catenin-mediated) Wnt signaling in hematolymphopoiesis has been studied extensively, little is known of the potential importance of non-canonical Wnt signals in hematopoietic cells. Wnt4 is one of the Wnt proteins that can elicit non-canonical pathways. We have previously shown that retroviral overexpression of Wnt4 by hematopoietic cells increased thymic cellularity as well as the frequency of early thymic progenitors and bone marrow hematopoietic progenitor cells (HPCs). However, the molecular pathways responsible for its effect in HPCs are not known.

Methodology/principal findings: Here we report that Wnt4 stimulation resulted in the activation of the small GTPase Rac1 as well as Jnk kinases in an HPC cell line. Jnk activity was necessary, while β-catenin was dispensable, for the Wnt4-mediated expansion of primary fetal liver HPCs in culture. Furthermore, Jnk2-deficient and Wnt4 hemizygous mice presented lower numbers of HPCs in their bone marrow, and Jnk2-deficient HPCs showed increased rates of apoptosis. Wnt4 also improved HPC activity in a competitive reconstitution model in a cell-autonomous, Jnk2-dependent manner. Lastly, we identified Fz6 as a receptor for Wnt4 in immature HPCs and showed that the absence of Wnt4 led to a decreased expression of four polarity complex genes.

Conclusions/significance: Our results establish a functional role for non-canonical Wnt signaling in hematopoiesis through a pathway involving Wnt4, Fz6, Rac1 and Jnk kinases.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bone Marrow Cells / cytology
  • Calcium / metabolism
  • Cell Lineage
  • Cell Polarity*
  • Cell Proliferation
  • Cells, Cultured
  • Enzyme Activation
  • Frizzled Receptors / metabolism
  • Hematopoiesis
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / enzymology
  • Hematopoietic Stem Cells / metabolism*
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Mice
  • Mice, Inbred C57BL
  • NIH 3T3 Cells
  • Receptors, G-Protein-Coupled / metabolism
  • Signal Transduction*
  • Wnt Proteins / metabolism*
  • Wnt4 Protein


  • Frizzled Receptors
  • Fzd6 protein, mouse
  • Receptors, G-Protein-Coupled
  • Wnt Proteins
  • Wnt4 Protein
  • Wnt4 protein, mouse
  • JNK Mitogen-Activated Protein Kinases
  • Calcium