Glycogen synthase kinase 3, circadian rhythms, and bipolar disorder: a molecular link in the therapeutic action of lithium

BACKGROUND: Bipolar disorder (BPD) is a widespread condition characterized by recurring states of mania and depression. Lithium, a direct inhibitor of glycogen synthase kinase 3 (GSK3) activity, and a mainstay in BPD therapeutics, has been proposed to target GSK3 as a mechanism of mood stabilization. In addition to mood imbalances, patients with BPD often suffer from circadian disturbances. GSK3, an essential kinase with widespread roles in development, cell survival, and metabolism has been demonstrated to be an essential component of the Drosophila circadian clock. We sought to investigate the role of GSK3 in the mammalian clock mechanism, as a possible mediator of lithium's therapeutic effects. METHODS: GSK3 activity was decreased in mouse embryonic fibroblasts (MEFs) genetically and pharmacologically, and changes in the cyclical expression of core clock genes – mPer2 in particular – were examined. RESULTS: We demonstrate that genetic depletion of GSK3 in synchronized oscillating MEFs results in a significant delay in the periodicity of the endogenous clock mechanism, particularly in the cycling period of mPer2. Furthermore, we demonstrate that pharmacological inhibition of GSK3 activity by kenpaullone, a known antagonist of GSK3 activity, as well as by lithium, a direct inhibitor of GSK3 and the most common treatment for BPD, induces a phase delay in mPer2 transcription that resembles the effect observed with GSK3 knockdown. CONCLUSION: These results confirm GSK3 as a plausible target of lithium action in BPD therapeutics, and suggest the circadian clock mechanism as a significant modulator of lithium's clinical benefits

Time- and Concentration-Dependent Response of the Drosophila Antenna Imaginal Disc to Antennapedia

AbstractThe response of the antenna imaginal disc to ectopic Antennapedia gene expression was explored in a heat shock Antennapedia (hsAntp) transgenic strain and in strains doubly transgenic for hsAntp and downstream enhancer trap targets, The distal to proximal changes in morphological transformation in response to Antennapedia product at different developmental stages were correlated with changing expression patterns of transgene targets from antenna to leg-like patterns. Dose-response studies indicated changing thresholds of response to Antennapedia. At particular stages and doses of Antennapedia product, cell differentiation of leg bristles was uncoupled from transformation of the third antennal segment to tarsus. The results suggest that determination for bristle type does not depend on a prior determination decision for organ type. The results also provide an avenue for exploring the nature of "competence" at cellular and molecular levels

Regulation of the protein kinase activity of ShaggyZeste-white3by components of the Wingless pathway inDrosophilacells and embryos.

A partially ruined monumental iwan from Aq Saray Palace is all that has survived from the legendary palaces of Timur (reg. 1370–1405) in central Asia. Located in the northeastern part of Shahrisabz (lit. "Green City"), now in Uzbekistan, the construction of Aq Saray (lit. "White Palace") was ordered by Timur in 1380 after a victorious battle with Urgench...The excavations on the site have not been adequate enough to reveal the plan of the complex; it is not clear where the remaining iwan was located in relation to other parts of the palace...The standing iwan is one of the largest built in the Islamic era surviving to date. Although it spans 22 meters and is 30 meters tall, it is estimated that the original vault was as tall as 50 meters. Facing north toward Samarqand, the remaining structure consists of two consecutive rectangular spaces with collapsed vaults. The larger iwan is framed by a portal screen and is flanked by two truncated cylindrical towers. (Historical sources suggest the original height of the towers to have been 60 to 70 meters.) The second narrower iwan, 13 meters in width, was closed by an arched wall. Source: Archnetexterior, 200

Correction: The Rho Guanine Nucleotide Exchange Factor DRhoGEF2 Is a Genetic Modifier of the PI3K Pathway in Drosophila.

[This corrects the article DOI: 10.1371/journal.pone.0152259.]

Rho signaling suppresses the PTEN-overexpression eye phenotype via dPKB/dAkt activation.

<p>(A) Scanning electronic micrograph of adult eyes from (I) <i>GMR-GAL4/+</i>, (II) <i>GMR-GAL4>UAS-PTEN/CyO</i>, (III) <i>GMR-GAL4>UAS-PTEN/DRhoGEF2</i>^<i>04291</i>, and (IV) <i>GMR-GAL4>UAS-PTEN/DRhoGEF2</i>^{<i>e03784</i>}. Scale bar = 200 μm. (B) Toluidine blue-stained longitudinal retinal sections of adult eyes from (I) <i>GMR-GAL4/+</i> and (II) <i>GMR-GAL4>UAS-PTEN</i> and (III) <i>GMR-GAL4>UAS-PTEN/DRhoGEF2</i>^<i>04291</i>. (C) Scanning electronic micrograph of adult eyes from (I) <i>GMR-GAL>UAS-PTEN</i> and (II) <i>GMR-GAL4>UASPTEN/Rho</i>^{<i>E3</i>.<i>10</i>}. Scale bar = 200 m. μ(D) Scanning electronic micrograph of adult eyes from (I) <i>GMR-GAL4>UAS-PTEN</i> and (II) <i>w67c23P{EPgy2}RhoGAPp190EY08765/+;GMR-GAL4>UAS-PTEN/+</i>. Scale bar = 200 μm. (D) dPKB/dAkt phosphorylation in the 3^rd instar larval eye discs from the wild type controls (<i>Canton-S</i>; <i>ry</i>^<i>506</i>, and <i>w1118</i>) and the mutants (<i>DRhoGEF2</i>^<i>04291</i><i>/CyO</i>, <i>DRhoGEF2</i>^<i>e0378</i><i>/CyO</i>, <i>Rho1</i>^{<i>E3</i>.<i>10</i>}<i>/CyO</i>, and <i>Drok</i>^<i>1</i><i>/FM7</i>), representative of three independent experiments.</p

The lethality rescue of DRhoGE2 homozygous mutant alleles by DRhoGEF2 and its mammalian orthologs.

<p>The lethality rescue of DRhoGE2 homozygous mutant alleles by DRhoGEF2 and its mammalian orthologs.</p