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PMID:18953410

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Citation

Andersson, ER, Prakash, N, Cajanek, L, Minina, E, Bryja, V, Bryjova, L, Yamaguchi, TP, Hall, AC, Wurst, W and Arenas, E (2008) Wnt5a regulates ventral midbrain morphogenesis and the development of A9-A10 dopaminergic cells in vivo. PLoS ONE 3:e3517

Abstract

Wnt5a is a morphogen that activates the Wnt/planar cell polarity (PCP) pathway and serves multiple functions during development. PCP signaling controls the orientation of cells within an epithelial plane as well as convergent extension (CE) movements. Wnt5a was previously reported to promote differentiation of A9-10 dopaminergic (DA) precursors in vitro. However, the signaling mechanism in DA cells and the function of Wnt5a during midbrain development in vivo remains unclear. We hereby report that Wnt5a activated the GTPase Rac1 in DA cells and that Rac1 inhibitors blocked the Wnt5a-induced DA neuron differentiation of ventral midbrain (VM) precursor cultures, linking Wnt5a-induced differentiation with a known effector of Wnt/PCP signaling. In vivo, Wnt5a was expressed throughout the VM at embryonic day (E)9.5, and was restricted to the VM floor and basal plate by E11.5-E13.5. Analysis of Wnt5a-/- mice revealed a transient increase in progenitor proliferation at E11.5, and a precociously induced NR4A2+ (Nurr1) precursor pool at E12.5. The excess NR4A2+ precursors remained undifferentiated until E14.5, when a transient 25% increase in DA neurons was detected. Wnt5a-/- mice also displayed a defect in (mid)brain morphogenesis, including an impairment in midbrain elongation and a rounded ventricular cavity. Interestingly, these alterations affected mostly cells in the DA lineage. The ventral Sonic hedgehog-expressing domain was broadened and flattened, a typical CE phenotype, and the domains occupied by Ngn2+ DA progenitors, NR4A2+ DA precursors and TH+ DA neurons were rostrocaudally reduced and laterally expanded. In summary, we hereby describe a Wnt5a regulation of Wnt/PCP signaling in the DA lineage and provide evidence for multiple functions of Wnt5a in the VM in vivo, including the regulation of VM morphogenesis, DA progenitor cell division, and differentiation of NR4A2+ DA precursors.

Links

PubMed PMC2568809 Online version:10.1371/journal.pone.0003517

Keywords

Animals; Cell Differentiation/genetics; Cell Polarity/genetics; Cell Polarity/physiology; Cell Proliferation; Dopamine/metabolism; Embryo, Mammalian; Female; Mesencephalon/embryology; Mesencephalon/metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Biological; Morphogenesis/genetics; Neurogenesis/genetics; Neurons/metabolism; Neurons/physiology; Pregnancy; Wnt Proteins/genetics; Wnt Proteins/metabolism; Wnt Proteins/physiology; rac1 GTP-Binding Protein/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:WNT5A

involved_in

GO:0090630: activation of GTPase activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:WNT5A

acts_upstream_of_or_within

GO:0001736: establishment of planar polarity

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1857617

P

  • occurs_in:(EMAPA:16975)

Seeded From UniProt

complete

MOUSE:WNT5A

acts_upstream_of_or_within

GO:0001736: establishment of planar polarity

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1857617

P

occurs_in:(EMAPA:16975)

Seeded From UniProt

complete

MOUSE:WNT5A

acts_upstream_of_or_within

GO:0060071: Wnt signaling pathway, planar cell polarity pathway

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:97845

P

Seeded From UniProt

complete

MOUSE:WNT5A

acts_upstream_of_or_within

GO:0071542: dopaminergic neuron differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1857617

P

  • occurs_in:(EMAPA:16974)
  • results_in_acquisition_of_features_of:(CL:0000700)

Seeded From UniProt

complete

MOUSE:WNT5A

acts_upstream_of_or_within

GO:0071542: dopaminergic neuron differentiation

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:97845

P

Seeded From UniProt

complete

MOUSE:WNT5A

involved_in

GO:1904934: negative regulation of cell proliferation in midbrain

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:WNT5A

involved_in

GO:0090630: activation of GTPase activity

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_regulation_target:(UniProtKB:P63001)
  • part_of:(GO:0071542)

Seeded From UniProt

complete

MOUSE:WNT5A

involved_in

GO:1904948: midbrain dopaminergic neuron differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RAC1

acts_upstream_of_or_within

GO:0060071: Wnt signaling pathway, planar cell polarity pathway

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:98958

P

Seeded From UniProt

complete

MOUSE:RAC1

acts_upstream_of_or_within

GO:0071542: dopaminergic neuron differentiation

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:98958

P

Seeded From UniProt

complete

MOUSE:RAC1

involved_in

GO:1904948: midbrain dopaminergic neuron differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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