Liver X receptors and oxysterols promote ventral midbrain neurogenesis in vivo and in human embryonic stem cells

Cell Stem Cell. 2009 Oct 2;5(4):409-19. doi: 10.1016/j.stem.2009.08.019.


Control over progenitor proliferation and neurogenesis remains a key challenge for stem cell neurobiology and a prerequisite for successful stem cell replacement therapies for neurodegenerative diseases like Parkinson's disease (PD). Here, we examined the function of two nuclear receptors, liver X receptors (Lxralpha and beta) and their ligands, oxysterols, as regulators of cell division, ventral midbrain (VM) neurogenesis, and dopaminergic (DA) neuron development. Deletion of Lxrs reduced cell cycle progression and VM neurogenesis, resulting in decreased DA neurons at birth. Activation of Lxrs with oxysterol ligands increased the number of DA neurons in mouse embryonic stem cells (ESCs) and in wild-type but not Lxralphabeta(-/-) VM progenitor cultures. Likewise, oxysterol treatment of human ESCs (hESCs) during DA differentiation increased neurogenesis and the number of mature DA neurons, while reducing proliferating progenitors. Thus, Lxr ligands may improve current hESC replacement strategies for PD by selectively augmenting the generation of DA neurons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / drug effects
  • Cholesterol / analogs & derivatives*
  • Cholesterol / pharmacology*
  • Dopamine / metabolism
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / drug effects*
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization
  • Liver X Receptors
  • Mesencephalon / cytology*
  • Mesencephalon / drug effects
  • Mice
  • Neurogenesis / drug effects*
  • Neurogenesis / genetics
  • Orphan Nuclear Receptors / genetics
  • Orphan Nuclear Receptors / physiology*
  • Polymerase Chain Reaction


  • Liver X Receptors
  • NR1H3 protein, human
  • Nr1h3 protein, mouse
  • Orphan Nuclear Receptors
  • Cholesterol
  • Dopamine