Fzd7 (Frizzled-7) Expressed by Endothelial Cells Controls Blood Vessel Formation Through Wnt/β-Catenin Canonical Signaling.

Abstract OBJECTIVE: Vessel formation requires precise orchestration of a series of morphometric and molecular events controlled by a multitude of angiogenic factors and morphogens. Wnt/frizzled signaling is required for proper vascular formation. In this study, we investigated the role of the Fzd7 (frizzled-7) receptor in retinal vascular development and its relationship with the Wnt/β-catenin canonical pathway and Notch signaling. APPROACH AND RESULTS: Using transgenic mice, we demonstrated that Fzd7 is required for postnatal vascular formation. Endothelial cell (EC) deletion of fzd7 (fzd7ECKO) delayed retinal plexus formation because of an impairment in tip cell phenotype and a decrease in stalk cell proliferation. Dvl (dishevelled) proteins are a main component of Wnt signaling and play a functionally redundant role. We found that Dvl3 depletion in dvl1-/- mice mimicked the fzd7ECKO vascular phenotype and demonstrated that Fzd7 acted via β-catenin activation by showing that LiCl treatment rescued impairment in tip and stalk cell phenotypes induced in fzd7 mutants. Deletion of fzd7 or Dvl1/3 induced a strong decrease in Wnt canonical genes and Notch partners' expression. Genetic and pharmacological rescue strategies demonstrated that Fzd7 acted via β-catenin activation, upstream of Notch signaling to control Dll4 and Jagged1 EC expression. CONCLUSIONS: Fzd7 expressed by EC drives postnatal angiogenesis via activation of Dvl/β-catenin signaling and can control the integrative interaction of Wnt and Notch signaling during postnatal angiogenesis

Lack of insight may predict impaired decision making in manic patients.

OBJECTIVES: The tendency to engage in risky behaviours is a core feature of the manic episodes of bipolar disorder. The aim of this study was to establish whether this characteristic can be quantified with a laboratory measure of decision making [the Iowa Gambling Task (IGT)] and to determine clinical correlates of the IGT performance in mania. METHODS: Inpatients with acute mania (n = 45) and healthy volunteers (n = 45) were assessed on the IGT. Affective symptomatology was assessed with the Young Mania Rating Scale and Hamilton Depression Rating Scale, and item scores were subjected to factor analysis. Multivariate regression was used to assess clinical predictors of impaired decision making in the manic patients. RESULTS: On the IGT, manic patients selected more cards from the risky decks than healthy controls, and showed little capacity to learn from incurred losses. In a multivariate analysis, impaired decision making ability in the manic patients was significantly predicted by a symptom factor associated with lack of insight. CONCLUSIONS: Manic patients clearly show defects in decision making, which are strongly related to their lack of insight. Neural circuitry supporting effective decision making, including the ventromedial prefrontal cortex and somatosensory cortex, may be implicated in the pathophysiology of acute mania

Trait-related decision-making impairment in the three phases of bipolar disorder

Background: In bipolar disorder (BD), little is known about how deficits in neurocognitive functions such as decision-making are related to phase of illness. We predicted that manic, depressed, and euthymic bipolar patients (BPs) would display impaired decision-making, and we tested whether clinical characteristics could predict patients' decision-making performance. Methods: Subjects (N = 317; age range: 1865 years) including 167 BPs (45 manic and 32 depressed inpatients, and 90 euthymic outpatients) and 150 age-, IQ-, and gender-matched healthy control (HC) participants, were included within three university psychiatric hospitals using a cross-sectional design. The relationship between predictor variables and decision-making was assessed by one-step multivariate analysis. The main outcome measures were overall decision-making ability on the Iowa Gambling Task (IGT) and an index of sensitivity to punishment frequency. Results: Manic, depressed, and euthymic BPs selected significantly more cards from the risky decks than HCs (p <.001, p <.01, and p <.05, respectively), with no significant differences between the three BD groups. However, like HCs, BPs preferred decks that yielded infrequent penalties over those yielding frequent penalties. In multivariate analysis, decision-making impairment was significantly (p <.001) predicted by low level of education, high depressive scores, family history of BD, use of benzodiazepines, and nonuse of serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressants. Conclusions: BPs have a trait-related impairment in decision-making that does not vary across illness phase. However, some subtle differences between the BD groups in the individual deck analyses may point to subtle state influences on reinforcement mechanisms, in addition to a more fundamental trait impairment in risk-sensitive decision making. © 2011 Society of Biological Psychiatry

Trait-related decision-making impairment in the three phases of bipolar disorder.

BACKGROUND: In bipolar disorder (BD), little is known about how deficits in neurocognitive functions such as decision-making are related to phase of illness. We predicted that manic, depressed, and euthymic bipolar patients (BPs) would display impaired decision-making, and we tested whether clinical characteristics could predict patients' decision-making performance. METHODS: Subjects (N = 317; age range: 18-65 years) including 167 BPs (45 manic and 32 depressed inpatients, and 90 euthymic outpatients) and 150 age-, IQ-, and gender-matched healthy control (HC) participants, were included within three university psychiatric hospitals using a cross-sectional design. The relationship between predictor variables and decision-making was assessed by one-step multivariate analysis. The main outcome measures were overall decision-making ability on the Iowa Gambling Task (IGT) and an index of sensitivity to punishment frequency. RESULTS: Manic, depressed, and euthymic BPs selected significantly more cards from the risky decks than HCs (p < .001, p < .01, and p < .05, respectively), with no significant differences between the three BD groups. However, like HCs, BPs preferred decks that yielded infrequent penalties over those yielding frequent penalties. In multivariate analysis, decision-making impairment was significantly (p < .001) predicted by low level of education, high depressive scores, family history of BD, use of benzodiazepines, and nonuse of serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressants. CONCLUSIONS: BPs have a trait-related impairment in decision-making that does not vary across illness phase. However, some subtle differences between the BD groups in the individual deck analyses may point to subtle state influences on reinforcement mechanisms, in addition to a more fundamental trait impairment in risk-sensitive decision making

Sci signal

Endothelial cells serve as a barrier between blood and tissues. Maintenance of the endothelial cell barrier depends on the integrity of intercellular junctions, which is regulated by a polarity complex that includes the ζ isoform of atypical protein kinase C (PKCζ) and partitioning defective 3 (PAR3). We revealed that the E3 ubiquitin ligase PDZ domain-containing ring finger 3 (PDZRN3) regulated endothelial intercellular junction integrity. Endothelial cell-specific overexpression of Pdzrn3 led to early embryonic lethality with severe hemorrhaging and altered organization of endothelial intercellular junctions. Conversely, endothelial-specific loss of Pdzrn3 prevented vascular leakage in a mouse model of transient ischemic stroke, an effect that was mimicked by pharmacological inhibition of PKCζ. PDZRN3 regulated Wnt signaling and associated with a complex containing PAR3, PKCζ, and the multi-PDZ domain protein MUPP1 (Discs Lost-multi-PDZ domain protein 1) and targeted MUPP1 for proteasomal degradation in transfected cells. Transient ischemic stroke increased the ubiquitination of MUPP1, and deficiency of MUPP1 in endothelial cells was associated with decreased localization of PKCζ and PAR3 at intercellular junctions. In endothelial cells, Pdzrn3 overexpression increased permeability through a PKCζ-dependent pathway. In contrast, Pdzrn3 depletion enhanced PKCζ accumulation at cell-cell contacts and reinforced the cortical actin cytoskeleton under stress conditions. These findings reveal how PDZRN3 regulates vascular permeability through a PKCζ-containing complex