Abstract
β-catenin is a multi-functional protein that has an important role in the mature central nervous system; its dysfunction has been implicated in several neuropsychiatric disorders, including depression. Here we show that in mice β-catenin mediates pro-resilient and anxiolytic effects in the nucleus accumbens, a key brain reward region, an effect mediated by D2-type medium spiny neurons. Using genome-wide β-catenin enrichment mapping, we identify Dicer1—important in small RNA (for example, microRNA) biogenesis—as a β-catenin target gene that mediates resilience. Small RNA profiling after excising β-catenin from nucleus accumbens in the context of chronic stress reveals β-catenin-dependent microRNA regulation associated with resilience. Together, these findings establish β-catenin as a critical regulator in the development of behavioural resilience, activating a network that includes Dicer1 and downstream microRNAs. We thus present a foundation for the development of novel therapeutic targets to promote stress resilience.
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Acknowledgements
We thank O. Jabado and M. Mahajan for support and S. Borkan for providing β-catenin constructs. This work was supported by grants from the National Institute of Mental Health and the Hope for Depression Research Foundation (HDRF).
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Contributions
C.D. and J.F. conceived the project, designed research, conducted experiments, interpreted the results, and wrote the manuscript; H.S., M.S.M.-R., D.D.-W., K.S., R.B., B.L., E.R., P.K., V.V., D.F., C.P., E.C., J.K. and E.M. conducted experiments; S.G., C.T. provided reagents and tools; R.N. conducted experiments and provided reagents; N.S., X.L. performed bioinformatic analysis; L.S. performed and supervised bioinformatic analysis; E.J.N. conceived the project, designed and supervised research, interpreted the results, and wrote the manuscript. All authors discussed the results and commented on the manuscript.
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Extended data figures and tables
Extended Data Figure 1 Validation of HSV-β-catenin.
a, β-catenin mRNA levels following HSV-β-catenin versus HSV-GFP injection into NAc (*P < 0.05, two-tailed t-test, n = 3 per group). b, Top panel, subcellular fractionation of NAc lysates from HSV-GFP or HSV-β-catenin injected mice. Middle panel, representative western blots of data shown in panel a. CYT, cytosolic fraction; NUC, nuclear fraction (−chromatin); CHR, chromatin fraction. Bottom panel, IHC of nuclear β-catenin 5 days post-injection with HSV-β-catenin versus HSV-GFP (***P < 0.001, two-tailed t-test, n = 3 per group). c, β-catenin IP on virus-injected NAc. IP results are representative of 5 replications. All other data shown are representative of at least two experiments. Data are presented as mean and s.e.m.
Extended Data Figure 2 Other β-catenin manipulations.
a, Schematic of Cre-dependent HSV-lox-stop (LS1L)-β-catenin cassette. b, Validation of β-catenin knockdown in the NAc of floxed β-catenin mice (***P < 0.001, two-tailed t-test, n = 4 GFP, n = 5 Cre). c, Failure of dominant negative β-catenin to rescue social interaction as compared to GFP after previous excision of β-catenin from NAc in floxed β-catenin mice undergoing defeat (P > 0.05, two-tailed t-test, n = 7 per group). Data are presented as mean and s.e.m. All data shown are representative of at least two experiments.
Extended Data Figure 3 No effect of β-catenin deletion on baseline behaviours.
a, Social interaction (SI) in control, non-stressed animals (P > 0.05, two-tailed t-test, n = 5 per group). b, Total distance travelled in arena (P > 0.05, two-tailed t-test, n = 5 per group). c, Average velocity (P > 0.05, two-tailed t-test, n = 5 per group). Data are presented as mean and s.e.m. All data shown are representative of at least two experiments.
Extended Data Figure 4 Regulation of β-catenin signalling in human depression and after CSDS in mice.
a, Axin2 expression is suppressed in both medicated and unmedicated depressed patients, both groups of which were clinically depressed at their time of death (P < 0.01 one-way ANOVA, post-hoc test P > 0.05 between depressed unmedicated and medicated groups, *P < 0.01 for either depressed group versus control, n = 6 control, n = 5 unmedicated depressed, medicated depressed). b, Phospho-Ser 675 β-catenin and total β-catenin levels from mouse control, susceptible, and resilient NAc 48 h post CSDS (phospho-Ser 675: *P < 0.05, one-way ANOVA, post-hoc test susceptible versus resilient, n = 5 for control, susceptible, n = 8 for resilient). Data are presented as mean and s.e.m. Human data are from one experiment. All other data shown are representative of two experiments.
Extended Data Figure 5 Repeated optogenetic burst stimulation of VTA cell bodies has no effect on canonical β-catenin signalling in NAc.
Experiment was performed as in Fig. 2 with the exception of the optic fibre, which was placed above VTA for cell body stimulation (P > 0.05, two-tailed t-test, n = 8 per group). Data are presented as mean and s.e.m. Data are from one experiment.
Extended Data Figure 6 Genome-wide enrichment of H3K4me3 and H4K16ac binding in NAc at TSSs.
NGS plot was used to visualize binding patterns.
Extended Data Figure 7 Genome-wide pattern of H3K4me3 binding to genic regions in NAc under control, susceptible (defeat), and resilient mice.
Note the lack of difference across the three conditions. Data are from one experiment.
Extended Data Figure 8 Genome-wide pattern of H4K16ac binding to genic regions in NAc under control, susceptible (defeat), and resilient mice.
Note the lack of difference across the three conditions. Shading represents standard error. Data are from one experiment.
Extended Data Figure 9 Ingenuity pathway analysis (IPA) identifies a network of genes that show upregulated β-catenin binding at promoter regions in the NAc of resilient versus susceptible mice.
Nodes represent differentially regulated genes, with green meaning up in resilient versus susceptible and red meaning down in resilient versus susceptible. The blue arrows indicate that the direction of regulation is consistent with IPA prediction of an upregulated β-catenin network in resilience; for example, a blue arrow means that a target gene that would be expected to be upregulated by β-catenin is in fact upregulated in this list. In contrast, yellow arrows indicate that the regulation observed is inconsistent with expectations, while grey arrows indicate lack of pre-existing data to formulate expectations of β-catenin action. Left panel shows mostly expected regulation of the β-catenin network (that is, upregulation) in resilience; right panel shows non-specific changes occurring in a randomly chosen signal transducer and activator of transcription-4 (STAT4) network.
Extended Data Figure 10 Validation of local Dicer1 knockdown.
Note significant knockdown of Dicer expression in NAc after intra-NAc delivery of viral-Cre to floxed Dicer mice (*P < 0.05, two-tailed t-test, n = 7 GFP, n = 6 Cre). Data are presented as mean and s.e.m. and are representative of two experiments.
Supplementary information
Supplementary Information
This file contains Supplementary Tables 1-9 and Supplementary Notes. (PDF 608 kb)
Supplementary Data 1
β-catenin ChIP-seq dataset: contains peak lists from each of three conditions and three pair-wise differential peak lists. (XLSX 14694 kb)
Supplementary Data 2
H3K4me3 and H4K16 ChIP-seq datasets: contains differential peak lists as compared to control. (XLSX 555 kb)
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Dias, C., Feng, J., Sun, H. et al. β-catenin mediates stress resilience through Dicer1/microRNA regulation. Nature 516, 51–55 (2014). https://doi.org/10.1038/nature13976
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DOI: https://doi.org/10.1038/nature13976
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