Delayed dopaminergic neuron differentiation in Lrp6 mutant mice

Dev Dyn. 2010 Jan;239(1):211-21. doi: 10.1002/dvdy.22094.


Wnts are known to bind and activate multiple membrane receptors/coreceptors and to regulate dopaminergic (DA) neuron development and ventral midbrain (VM) morphogenesis. The low density lipoprotein receptor-related protein (Lrp6) is a Wnt co-receptor, yet it remains unclear whether Lrp6 is required for DA neuron development or VM morphogenesis. Lrp6 is expressed ubiquitously in the developing VM. In this study, we show that Lrp6(-/-) mice exhibit normal patterning, proliferation and cell death in the VM, but display a delay in the onset of DA precursor differentiation. A transient 50% reduction in tyrosine hydroxylase-positive DA neurons and in the expression of DA markers such as Nurr1 and Pitx3, as well as a defect in midbrain morphogenesis was detected in the mutant embryos at embryonic day 11.5. Our results, therefore, suggest a role for Lrp6 in the onset of DA neuron development in the VM as well as a role in midbrain morphogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bromodeoxyuridine
  • Cell Differentiation / genetics*
  • Cell Differentiation / physiology
  • Dopamine / metabolism*
  • Genotype
  • Homeodomain Proteins / metabolism
  • Immunohistochemistry
  • In Situ Hybridization
  • Mesencephalon / embryology*
  • Mice
  • Mice, Knockout
  • Microscopy, Confocal
  • Morphogenesis / genetics*
  • Neurons / cytology*
  • Neurons / metabolism
  • Nuclear Receptor Subfamily 4, Group A, Member 2 / metabolism
  • Transcription Factors / metabolism
  • Tyrosine 3-Monooxygenase / metabolism


  • Homeodomain Proteins
  • Nuclear Receptor Subfamily 4, Group A, Member 2
  • Transcription Factors
  • homeobox protein PITX3
  • Tyrosine 3-Monooxygenase
  • Bromodeoxyuridine
  • Dopamine