title: SFRP1 and SFRP2 dose-dependently regulate midbrain dopamine neuron development in vivo and in embryonic stem cells.
abstract: Secreted Frizzled related proteins (sFRPs) are a family of proteins that modulate Wnt signaling, which in turn regulates multiple aspects of ventral midbrain (VM) and dopamine (DA) neuron development. However, it is not known which Wnt signaling branch and what aspects of midbrain DA neuron development are regulated by sFRPs. Here, we show that sFRP1 and sFRP2 activate the Wnt/planar-cell-polarity/Rac1 pathway in DA cells. In the developing VM, sFRP1 and sFRP2 are expressed at low levels, and sFRP1-/- or sFRP2-/- mice had no detectable phenotype. However, compound sFRP1-/-;sFRP2-/- mutants revealed a Wnt/PCP phenotype similar to that previously described for Wnt5a-/- mice. This included an anteroposterior shortening of the VM, a lateral expansion of the Shh domain and DA lineage markers (Lmx1a and Th), as well as an accumulation of Nurr1+ precursors in the VM. In vitro experiments showed that, while very high concentrations of SFRP1 had a negative effect on cell survival, low/medium concentrations of sFRP1 or sFRP2 promoted the DA differentiation of progenitors derived from primary VM cultures or mouse embryonic stem cells (ESCs), mimicking the effects of Wnt5a. We thus conclude that the main function of sFRP1 and sFRP2 is to enhance Wnt/PCP signaling in DA cells and to regulate Wnt/PCP-dependent functions in midbrain development. Moreover, we suggest that low-medium concentrations of sFRPs may be used to enhance the DA differentiation of ESCs and improve their therapeutic application.
authors.affiliation: Laboratory of Molecular Neurobiology, Medical Biochemistry and Biophysics, Karolinska Institute, Scheeleväg 1, Stockholm, Sweden.
authors.forename: Julianna
authors.initials: J
authors.lastname: Kele
authors.forename: Emma R
authors.initials: ER
authors.lastname: Andersson
authors.forename: J Carlos
authors.initials: JC
authors.lastname: Villaescusa
authors.forename: Lukas
authors.initials: L
authors.lastname: Cajanek
authors.forename: Clare L
authors.initials: CL
authors.lastname: Parish
authors.forename: Sonia
authors.initials: S
authors.lastname: Bonilla
authors.forename: Enrique M
authors.initials: EM
authors.lastname: Toledo
authors.forename: Vitezslav
authors.initials: V
authors.lastname: Bryja
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Rubin
authors.forename: Akihiko
authors.initials: A
authors.lastname: Shimono
authors.forename: Ernest
authors.initials: E
authors.lastname: Arenas
mesh_terms: D000818:Animals; D059290:Dopaminergic Neurons / Q000166:cytology / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008636:Mesencephalon / Q000166:cytology / Q000196:embryology*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D051153:Wnt Proteins; C485539:Sfrp1 protein, mouse; D000094742:Secreted Frizzled-Related Proteins; C500646:Sfrp1 protein, rat; C491628:Sfrp2 protein, mouse; C503650:Sfrp2 protein, rat