D₂ Dopamine Receptors Colocalize Regulator of G-Protein Signaling 9-2 (RGS9-2) via the RGS9 DEP Domain, and RGS9 Knock-Out Mice Develop Dyskinesias Associated with Dopamine Pathways

Regulator of G-protein signaling 9-2 (RGS9-2), a member of the RGS family of Gα GTPase accelerating proteins, is expressed specifically in the striatum, which participates in antipsychotic-induced tardive dyskinesia and in levodopa-induced dyskinesia. We report that RGS9 knock-out mice develop abnormal involuntary movements when inhibition of dopaminergic transmission is followed by activation of D₂-like dopamine receptors (DRs). These abnormal movements resemble drug-induced dyskinesia more closely than other rodent models. Recordings from striatal neurons of these mice establish that activation of D₂-like DRs abnormally inhibits glutamate-elicited currents. We show that RGS9-2, via its DEP domain (for Disheveled, EGL-10, Pleckstrin homology), colocalizes with D₂DRs when coexpressed in mammalian cells. Recordings from oocytes coexpressing D₂DR or the m2 muscarinic receptor and G-protein-gated inward rectifier potassium channels show that RGS9-2, via its DEP domain, preferentially accelerates the termination of D₂DR signals. Thus, alterations in RGS9-2 may be a key factor in the pathway leading from D₂DRs to the side effects associated with the treatment both of psychoses and Parkinson's disease

D₂ Dopamine Receptors Colocalize Regulator of G-Protein Signaling 9-2 (RGS9-2) via the RGS9 DEP Domain, and RGS9 Knock-Out Mice Develop Dyskinesias Associated with Dopamine Pathways

Regulator of G-protein signaling 9-2 (RGS9-2), a member of the RGS family of Gα GTPase accelerating proteins, is expressed specifically in the striatum, which participates in antipsychotic-induced tardive dyskinesia and in levodopa-induced dyskinesia. We report that RGS9 knock-out mice develop abnormal involuntary movements when inhibition of dopaminergic transmission is followed by activation of D₂-like dopamine receptors (DRs). These abnormal movements resemble drug-induced dyskinesia more closely than other rodent models. Recordings from striatal neurons of these mice establish that activation of D₂-like DRs abnormally inhibits glutamate-elicited currents. We show that RGS9-2, via its DEP domain (for Disheveled, EGL-10, Pleckstrin homology), colocalizes with D₂DRs when coexpressed in mammalian cells. Recordings from oocytes coexpressing D₂DR or the m2 muscarinic receptor and G-protein-gated inward rectifier potassium channels show that RGS9-2, via its DEP domain, preferentially accelerates the termination of D₂DR signals. Thus, alterations in RGS9-2 may be a key factor in the pathway leading from D₂DRs to the side effects associated with the treatment both of psychoses and Parkinson's disease

Modulation of the β-Catenin Signaling Pathway by the Dishevelled-Associated Protein Hipk1

BACKGROUND:Wnts are evolutionarily conserved ligands that signal through beta-catenin-dependent and beta-catenin-independent pathways to regulate cell fate, proliferation, polarity, and movements during vertebrate development. Dishevelled (Dsh/Dvl) is a multi-domain scaffold protein required for virtually all known Wnt signaling activities, raising interest in the identification and functions of Dsh-associated proteins. METHODOLOGY:We conducted a yeast-2-hybrid screen using an N-terminal fragment of Dsh, resulting in isolation of the Xenopus laevis ortholog of Hipk1. Interaction between the Dsh and Hipk1 proteins was confirmed by co-immunoprecipitation assays and mass spectrometry, and further experiments suggest that Hipk1 also complexes with the transcription factor Tcf3. Supporting a nuclear function during X. laevis development, Myc-tagged Hipk1 localizes primarily to the nucleus in animal cap explants, and the endogenous transcript is strongly expressed during gastrula and neurula stages. Experimental manipulations of Hipk1 levels indicate that Hipk1 can repress Wnt/beta-catenin target gene activation, as demonstrated by beta-catenin reporter assays in human embryonic kidney cells and by indicators of dorsal specification in X. laevis embryos at the late blastula stage. In addition, a subset of Wnt-responsive genes subsequently requires Hipk1 for activation in the involuting mesoderm during gastrulation. Moreover, either over-expression or knock-down of Hipk1 leads to perturbed convergent extension cell movements involved in both gastrulation and neural tube closure. CONCLUSIONS:These results suggest that Hipk1 contributes in a complex fashion to Dsh-dependent signaling activities during early vertebrate development. This includes regulating the transcription of Wnt/beta-catenin target genes in the nucleus, possibly in both repressive and activating ways under changing developmental contexts. This regulation is required to modulate gene expression and cell movements that are essential for gastrulation

Synaptic Wnt signaling—a contributor to major psychiatric disorders?

Wnt signaling is a key pathway that helps organize development of the nervous system. It influences cell proliferation, cell fate, and cell migration in the developing nervous system, as well as axon guidance, dendrite development, and synapse formation. Given this wide range of roles, dysregulation of Wnt signaling could have any number of deleterious effects on neural development and thereby contribute in many different ways to the pathogenesis of neurodevelopmental disorders. Some major psychiatric disorders, including schizophrenia, bipolar disorder, and autism spectrum disorders, are coming to be understood as subtle dysregulations of nervous system development, particularly of synapse formation and maintenance. This review will therefore touch on the importance of Wnt signaling to neurodevelopment generally, while focusing on accumulating evidence for a synaptic role of Wnt signaling. These observations will be discussed in the context of current understanding of the neurodevelopmental bases of major psychiatric diseases, spotlighting schizophrenia, bipolar disorder, and autism spectrum disorder. In short, this review will focus on the potential role of synapse formation and maintenance in major psychiatric disorders and summarize evidence that defective Wnt signaling could contribute to their pathogenesis via effects on these late neural differentiation processes

Dact1 presomitic mesoderm expression oscillates in phase with Axin2 in the somitogenesis clock of mice.

During segmentation (somitogenesis) in vertebrate embryos, somites form in a rostral-to-caudal sequence according to a species-specific rhythm called the somitogenesis clock. The expression of genes participating in somitogenesis oscillates in the presomitic mesoderm (PSM) in time with this clock. We previously reported that the Dact1 gene (aka Dpr1/Frd1/ThyEx3), which encodes a Dishevelled-binding intracellular regulator of Wnt signaling, is prominently expressed in the PSM as well as in a caudal-rostral gradient across the somites of mouse embryos. This observation led us to examine whether Dact1 expression oscillates in the PSM. We have found that Dact1 PSM expression does indeed oscillate in time with the somitogenesis clock. Consistent with its known signaling functions and with the "clock and wavefront" model of signal regulation during somitogenesis, the oscillation of Dact1 occurs in phase with the Wnt signaling component Axin2, and out of phase with the Notch signaling component Lfng

Dact1 presomitic mesoderm expression oscillates in phase with Axin2 in the somitogenesis clock of mice.

During segmentation (somitogenesis) in vertebrate embryos, somites form in a rostral-to-caudal sequence according to a species-specific rhythm called the somitogenesis clock. The expression of genes participating in somitogenesis oscillates in the presomitic mesoderm (PSM) in time with this clock. We previously reported that the Dact1 gene (aka Dpr1/Frd1/ThyEx3), which encodes a Dishevelled-binding intracellular regulator of Wnt signaling, is prominently expressed in the PSM as well as in a caudal-rostral gradient across the somites of mouse embryos. This observation led us to examine whether Dact1 expression oscillates in the PSM. We have found that Dact1 PSM expression does indeed oscillate in time with the somitogenesis clock. Consistent with its known signaling functions and with the "clock and wavefront" model of signal regulation during somitogenesis, the oscillation of Dact1 occurs in phase with the Wnt signaling component Axin2, and out of phase with the Notch signaling component Lfng

Three Dact gene family members are expressed during embryonic development and in the adult brains of mice

Members of the Dact protein family initially were identified through binding to Dishevelled (Dvl), a cytoplasmic protein central to Wnt signaling. During mouse development, Dact1 is detected in the presomitic mesoderm and somites during segmentation, in the limb bud mesenchyme and other mesoderm-derived tissues, and in the central nervous system (CNS). Dact2 expression is most prominent during organogenesis of the thymus, kidneys, and salivary glands, with much lower levels in the somites and in the developing CNS. Dact3, not previously described in any organism, is expressed in the ventral region of maturing somites, limb bud and branchial arch mesenchyme, and in the embryonic CNS; of the three paralogs, it is the most highly expressed in the adult cerebral cortex. These data are consistent with studies in other vertebrates showing that Dact paralogs have distinct signaling and developmental roles and suggest they may differentially contribute to postnatal brain physiology

Acute exacerbation of irritable bowel syndrome prevented by prn oral triptan

We report a case of irritable bowel syndrome (IBS), diarrhea subtype, characterized by daily 'morning rush' and episodic acute exacerbations brought on by common IBS trigger foods including insoluble fiber, red wine and large/rich meals. The patient also had a history of migraine headaches, and a family history suggesting a common diathesis for both disorders. Given hypothesized contributions to IBS from dysregulation of the enteric serotonergic system, a trial of low-dose triptan medication was implemented in the context of the patient's known IBS triggers, with highly satisfactory results

Dapper Antagonist of Catenin-1 Cooperates with Dishevelled-1 during Postsynaptic Development in Mouse Forebrain GABAergic Interneurons

<div><p>Synaptogenesis has been extensively studied along with dendritic spine development in glutamatergic pyramidal neurons, however synapse development in cortical interneurons, which are largely aspiny, is comparatively less well understood. Dact1, one of 3 paralogous Dact (Dapper/Frodo) family members in mammals, is a scaffold protein implicated in both the Wnt/β-catenin and the Wnt/Planar Cell Polarity pathways. We show here that Dact1 is expressed in immature cortical interneurons. Although Dact1 is first expressed in interneuron precursors during proliferative and migratory stages, constitutive <i>Dact1</i> mutant mice have no major defects in numbers or migration of these neurons. However, cultured cortical interneurons derived from these mice have reduced numbers of excitatory synapses on their dendrites. We selectively eliminated Dact1 from mouse cortical interneurons using a conditional knock-out strategy with a Dlx-I12b enhancer-Cre allele, and thereby demonstrate a cell-autonomous role for Dact1 during postsynaptic development. Confirming this cell-autonomous role, we show that synapse numbers in Dact1 deficient cortical interneurons are rescued by virally-mediated re-expression of Dact1 specifically targeted to these cells. Synapse numbers in these neurons are also rescued by similarly targeted expression of the Dact1 binding partner Dishevelled-1, and partially rescued by expression of Disrupted in Schizophrenia-1, a synaptic protein genetically implicated in susceptibility to several major mental illnesses. In sum, our results support a novel cell-autonomous postsynaptic role for Dact1, in cooperation with Dishevelled-1 and possibly Disrupted in Schizophrenia-1, in the formation of synapses on cortical interneuron dendrites.</p></div

Reduction of excitatory synapses in <i>Dact1</i> mutant cortical interneurons is cell-autonomous.

<p>Primary cortical cultures were prepared from postnatal day 0 Interneuron-specific <i>Dact1</i> mutant (<i>IDact1-KO</i>) (right) and control (left) brains, fixed at day <i>in vitro</i> 15, and pre- and post-synaptic co-localized puncta counted along GFP labeled primary dendrites from the cell soma to the first major branch point (arrowheads). VGAT/Gephyrin (inhibitory, <b>A</b>) and Vglut1/PSD95 (excitatory, <b>A</b>') co-localized puncta (arrowheads) along the GFP+ dendrite in control (left) and <i>IDact1-KO</i> (right) mice. Quantification of co-localized inhibitory (<b>B</b>) and excitatory (<b>B</b>') pre- and postsynaptic puncta in control (open bars) and <i>IDact1-KO</i> mutants (closed bars). Data shown are mean ± sem of at least 2 independent experiments, collected from at least 2 mice per genotype, 10–15 neurons per animal. ***<i>p</i><0.001; n.s., not significant. Scale bars = 10 µm.</p