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-cellpolarity/Rac1 pathway in DA cells. In the developing VM, sFRP1 and sFRP2 are expressed at low levels, and sFRP12/ 2 or sFRP22/2 mice had no detectable phenotype. However, compound sFRP12/2;sFRP22/2 mutants revealed a Wnt/PCP phenotype similar to that previously described for Wnt5a2/2 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 Nurr11 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 lowmedium concentrations of sFRPs may be used to enhance the DA differentiation of ESCs and improve their therapeutic application. STEM CELLS 2012;30:865-875 Disclosure of potential conflicts of interest is found at the end of this article.

BMP and TGF-β pathway mediators are critical upstream regulators of Wnt signaling during midbrain dopamine differentiation in human pluripotent stem cells

“…5B–D). Conversely, the addition of exogenous human recombinant Sfrp1 did not significantly change Wnt1–Lmx1a signaling, although a small rise in expression was noted at 100 ng/ml (data not shown), as in other studies (Kele et al, 2012; Schwartz et al, 2012). …”

Computationally efficient permutation-based confidence interval estimation for tail-area FDR

“…For example, the two genes with the smallest p -values are secreted Frizzled-related proteins, Sfrp1 and Sfrp4 ( p = 1.1e-5 and 3.1e-5, respectively), known to be involved in wnt signaling (Bovolenta et al, 2008) as well as dopamine neuron development (Kele et al, 2012). Wnt signaling has been linked to pathologies, mood and mental disorders, as well as neurodegenerative disease (Oliva et al, 2013), all of which commonly include sleep indications as comorbidities.…”

Acute Simian Varicella Virus Infection Causes Robust and Sustained Changes in Gene Expression in the Sensory Ganglia

“…(98) as well as neuronal gene expression through its interaction with eukaryotic elongation factor 2 kinase (eEF2K, FC of 3) (99). Other interesting DEGs that were associated with nervous system development include secreted frizzled-related protein 2 (SFRP2, FC of 35, important in neuron development [100]), C-C motif chemokine ligand 19 (CCL19, FC of 29, important for lymphocyte recirculation and homing to lymphoid tissue [101]), and aquaporin 4 (AQP4, FC of 13, a water channel expressed in astrocytes [102]). The most downregulated DEGs that mapped to the GO term "nervous system development" include GFAP (FC of 59), SFRP2 (FC of 35), MOBP (FC of 26), CPLX1 (FC of 18), and patatin-like phospholipase domain-containing 2 (PNPLA2, FC of 14).…”