Interactions of Wnt/ -Catenin Signaling and Sonic Hedgehog Regulate the Neurogenesis of Ventral Midbrain Dopamine Neurons

Department of Pathology, University of California, San Francisco and Pathology Service, Veterans Affairs Medical Center, San Francisco, California 94121, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 07/2010; 30(27):9280-91. DOI: 10.1523/JNEUROSCI.0860-10.2010
Source: PubMed


Signaling mechanisms involving Wnt/beta-catenin and sonic hedgehog (Shh) are known to regulate the development of ventral midbrain (vMB) dopamine neurons. However, the interactions between these two mechanisms and how such interactions can be targeted to promote a maximal production of dopamine neurons are not fully understood. Here we show that conditional mouse mutants with region-specific activation of beta-catenin signaling in vMB using the Shh-Cre mice show a marked expansion of Sox2-, Ngn2-, and Otx2-positive progenitors but perturbs their cell cycle exit and reduces the generation of dopamine neurons. Furthermore, activation of beta-catenin in vMB also results in a progressive loss of Shh expression and Shh target genes. Such antagonistic effects between the activation of Wnt/beta-catenin and Shh can be recapitulated in vMB progenitors and in mouse embryonic stem cell cultures. Notwithstanding these antagonistic interactions, cell-type-specific activation of beta-catenin in the midline progenitors using the tyrosine hydroxylase-internal ribosomal entry site-Cre (Th-IRES-Cre) mice leads to increased dopaminergic neurogenesis. Together, these results indicate the presence of a delicate balance between Wnt/beta-catenin and Shh signaling mechanisms in the progression from progenitors to dopamine neurons. Persistent activation of beta-catenin in early progenitors perturbs their cell cycle progression and antagonizes Shh expression, whereas activation of beta-catenin in midline progenitors promotes the generation of dopamine neurons.

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    • "nase - 3 beta ; NPCs , neu - ral precursor cells ; SD , standard deviation . plays a potential role in mood disorders and regulates various neurobiological functions , including axon and dendrite remod - elling and development , synaptogenesis , neuroplasticity , and neurogenesis ( Hirabayashi et al . , 2004 ; Lie et al . , 2005 ; Clevers , 2006 ; Tang et al . , 2010 ; Maguschak and Ressler , 2011 , 2012 ) . Inhibition of GSK - 3 with a small molecule , NP03112 , induced neurogenesis in the dentate gyri of the hippocampi of adult rats ( Morales - Garcia et al . , 2012 ) . GSK - 3 promotes apoptotic signal - ing in cultured neural precursor cells derived from embryonic mouse brains subjected to apopt"
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    ABSTRACT: It is generally accepted that chronic treatment with antidepressants increases hippocampal neurogenesis, but the molecular mechanisms underlying their effects are unknown. Recently, glycogen synthase kinase-3 beta (GSK-3β)/β-catenin signalling was shown to be involved in the mechanism of how antidepressants might influence hippocampal neurogenesis. The aim of this study was to determine whether GSK-3β/β-catenin signalling is involved in the alteration of neurogenesis as a result of treatment with fluoxetine, a selective serotonin reuptake inhibitor. The mechanisms involved in fluoxetine's regulation of GSK-3β/β-catenin signalling pathway were also examined. Our results demonstrated that fluoxetine increased the proliferation of embryonic neural precursor cells (NPCs) by upregulating the phosphorylation of Ser9 on GSK-3β and increasing the level of nuclear β-catenin. The overexpression of a stabilised β-catenin protein (ΔN89 β-catenin) significantly increased NPC proliferation, while inhibition of β-catenin expression in NPCs led to a significant decrease in the proliferation and reduced the proliferative effects induced by fluoxetine. The effects of fluoxetine-induced upregulation of both phosphorylation of Ser9 on GSK-3β and nuclear β-catenin were significantly prevented by the 5-hydroxytryptamine-1A (5-HT1A) receptor antagonist WAY-100635. The results demonstrate that fluoxetine may increase neurogenesis via the GSK-3β/β-catenin signalling pathway that links postsynaptic 5-HT1A receptor activation. © The Author 2014. Published by Oxford University Press on behalf of CINP.
    The International Journal of Neuropsychopharmacology 12/2014; 18(5). DOI:10.1093/ijnp/pyu099 · 4.01 Impact Factor
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    • "Furthermore, studies utilizing gene inducible fate mapping (GIFM) to mark the Shh and Gli1 lineages at E7.5–E11.5 showed that in mdDA neurons Gli1 and Shh have been expressed and thus might contribute to early mdDA cell differentiation [15]–[17]. On the other hand, some studies indicate that SHH does not promote a DA cell fate, but inhibits progenitors to acquire a DA cell-fate [18]–[20]. WNT-β-catenin signaling is thought to inhibit SHH in the ventral midline of the FP of the embryonic midbrain, allowing for neurogenesis and DA differentiation [19]. "
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    ABSTRACT: Sonic Hedgehog (SHH) and WNT proteins are key regulators in many developmental processes, like embryonic patterning and brain development. In the brain, SHH is expressed in a gradient starting in the floor plate (FP) progressing ventrally in the midbrain, where it is thought to be involved in the development and specification of mesodiencephalic dopaminergic (mdDA) neurons. GLI2A-mediated SHH-signaling induces the expression of Gli1, which is inhibited when cells start expressing SHH themselves. To determine whether mdDA neurons receive GLI2A-mediated SHH-signaling during differentiation, we used a BAC-transgenic mouse model expressing eGFP under the control of the Gli1 promoter. This mouse-model allowed for mapping of GLI2A-mediated SHH-signaling temporal and spatial in the mouse midbrain. Since mdDA neurons are born from E10.5, peaking at E11.0-E12.0, we examined Gli1-eGFP embryos at E11.5, E12.5, and E13.5, indicating whether Gli1 was induced before or during mdDA development and differentiation. Our data indicate that GLI2A-mediated SHH-signaling is not involved in mdDA neuronal differentiation. However, it appears to be involved in the differentiation of neurons which make up a subset of the red nucleus (RN). In order to detect whether mdDA neuronal differentiation may be under the control of canonical WNT-signaling, we used a transgenic mouse-line expressing LacZ under the influence of stable β-catenin. Here, we show that TH+ neurons of the midbrain receive canonical WNT-signaling during differentiation. Therefore, we suggest that early SHH-signaling is indirectly involved in mdDA development through early patterning of the midbrain area, whereas canonical WNT-signaling is directly involved in the differentiation of the mdDA neuronal population.
    PLoS ONE 05/2014; 9(5):e97926. DOI:10.1371/journal.pone.0097926 · 3.23 Impact Factor
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    • "Four of the 17 pathways enriched in cells expressing EWS/WT1 + KTS involved genes from Wnt and Sonic Hedgehog activation pathways (Figure  5C). There is significant overlap of genes in the Wnt and Sonic Hedgehog genesets, and indeed interactions between the functions of these gene sets [30]. Wnt7b was observed to be in the top 40 genes up-regulated in cells expressing EWS/WT1 + KTS compared to eGFP. "
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    BMC Cancer 12/2013; 13(1):585. DOI:10.1186/1471-2407-13-585 · 3.36 Impact Factor
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