Liver X receptors and oxysterols promote ventral midbrain neurogenesis in vivo and in human embryonic stem cells.
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.
Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Center for Developmental Biology and Regenerative Medicine, Karolinska Institute, Stockholm, Sweden.
Paola
P
Sacchetti
Kyle M
KM
Sousa
Anita C
AC
Hall
Isabel
I
Liste
Knut R
KR
Steffensen
Spyridon
S
Theofilopoulos
Clare L
CL
Parish
Carin
C
Hazenberg
Lars Ahrlund
LA
Richter
Outti
O
Hovatta
Jan-Ake
JA
Gustafsson
Ernest
E
Arenas
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D000071518:Liver X Receptors; D008636:Mesencephalon / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D055495:Neurogenesis / Q000187:drug effects* / Q000235:genetics; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000502:physiology*; D016133:Polymerase Chain Reaction
D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D002784:Cholesterol; D004298:Dopamine