Wnt5a cooperates with canonical Wnts to generate midbrain dopaminergic neurons in vivo and in stem cells

Proc Natl Acad Sci U S A. 2013 Feb 12;110(7):E602-10. doi: 10.1073/pnas.1208524110. Epub 2013 Jan 16.


Wnts are a family of secreted proteins that regulate multiple steps of neural development and stem cell differentiation. Two of them, Wnt1 and Wnt5a, activate distinct branches of Wnt signaling and individually regulate different aspects of midbrain dopaminergic (DA) neuron development. However, several of their functions and interactions remain to be elucidated. Here, we report that loss of Wnt1 results in loss of Lmx1a and Ngn2 expression, as well as agenesis of DA neurons in the midbrain floor plate. Remarkably, a few ectopic DA neurons still emerge in the basal plate of Wnt1(-/-) mice, where Lmx1a is ectopically expressed. These results indicate that Wnt1 orchestrates DA specification and neurogenesis in vivo. Analysis of Wnt1(-/-);Wnt5a(-/-) mice revealed a greater loss of Nurr1(+) cells and DA neurons than in single mutants, indicating that Wnt1 and Wnt5a interact genetically and cooperate to promote midbrain DA neuron development in vivo. Our results unravel a functional interaction between Wnt1 and Wnt5a resulting in enhanced DA neurogenesis. Taking advantage of these findings, we have developed an application of Wnts to improve the generation of midbrain DA neurons from neural and embryonic stem cells. We thus show that coordinated Wnt actions promote DA neuron development in vivo and in stem cells and suggest that coordinated Wnt administration can be used to improve DA differentiation of stem cells and the development of stem cell-based therapies for Parkinson's disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cell Count
  • Cell Differentiation / physiology
  • Dopaminergic Neurons / metabolism
  • Dopaminergic Neurons / physiology*
  • Immunohistochemistry
  • LIM-Homeodomain Proteins / metabolism
  • Mesencephalon / growth & development*
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins / metabolism
  • Neurogenesis / genetics
  • Neurogenesis / physiology*
  • Parkinson Disease / metabolism
  • Parkinson Disease / therapy
  • Stem Cells / cytology*
  • Stem Cells / metabolism
  • Transcription Factors / metabolism
  • Wnt Proteins / metabolism*
  • Wnt Signaling Pathway / physiology*
  • Wnt-5a Protein
  • Wnt1 Protein / deficiency
  • Wnt1 Protein / metabolism*


  • Basic Helix-Loop-Helix Transcription Factors
  • LIM-Homeodomain Proteins
  • Lmx1a protein, mouse
  • Nerve Tissue Proteins
  • Neurog2 protein, mouse
  • Transcription Factors
  • Wnt Proteins
  • Wnt-5a Protein
  • Wnt1 Protein
  • Wnt1 protein, mouse
  • Wnt5a protein, mouse