title: Wnt5a cooperates with canonical Wnts to generate midbrain dopaminergic neurons in vivo and in stem cells.
abstract: 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.
authors: Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Center of Developmental Biology for Regenerative Medicine, and Department of Cell and Molecular Biology, Karolinska Institute, Stockholm 171 77, Sweden.
authors: Emma R
authors: ER
authors: Andersson
authors: Carmen
authors: C
authors: Saltó
authors: J Carlos
authors: JC
authors: Villaescusa
authors: Lukas
authors: L
authors: Cajanek
authors: Shanzheng
authors: S
authors: Yang
authors: Lenka
authors: L
authors: Bryjova
authors: Irina I
authors: II
authors: Nagy
authors: Seppo J
authors: SJ
authors: Vainio
authors: Carmen
authors: C
authors: Ramirez
authors: Vitezslav
authors: V
authors: Bryja
authors: Ernest
authors: E
authors: Arenas
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002452:Cell Count; D002454:Cell Differentiation / Q000502:physiology; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000502:physiology*; D007150:Immunohistochemistry; D060850:LIM-Homeodomain Proteins / Q000378:metabolism; D008636:Mesencephalon / Q000254:growth & development*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology*; D010300:Parkinson Disease / Q000378:metabolism / Q000628:therapy; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D000071818:Wnt-5a Protein; D051155:Wnt1 Protein / Q000172:deficiency / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D060850:LIM-Homeodomain Proteins; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D051155:Wnt1 Protein; C489692:Lmx1a protein, mouse; C102938:Neurog2 protein, mouse; C495246:Wnt1 protein, mouse; C438615:Wnt5a protein, mouse