Isabelle Schmutz

Université de Fribourg, Brig, VS, Switzerland

Are you Isabelle Schmutz?

Claim your profile

Publications (32)

  • Source
    Isabelle Schmutz · Rohit Chavan · Jürgen A Ripperger · [...] · Urs Albrecht
    [Show abstract] [Hide abstract] ABSTRACT: Within the suprachiasmatic nucleus (SCN) of the hypothalamus, circadian timekeeping and resetting have been shown to be largely dependent on both membrane depolarization and intracellular second-messenger signaling. In both of these processes, voltage-gated calcium channels (VGCCs) mediate voltage-dependent calcium influx, which propagates neural impulses by stimulating vesicle fusion and instigates intracellular pathways resulting in clock gene expression. Through the cumulative actions of these processes, the phase of the internal clock is modified to match the light cycle of the external environment. To parse out the distinct roles of the L-type VGCCs, we analyzed mice deficient in Cav1.2 (Cacna1c) in brain tissue. We found that mice deficient in the Cav1.2 channel exhibited a significant reduction in their ability to phase-advance circadian behavior when subjected to a light pulse in the late night. Furthermore, the study revealed that the expression of Cav1.2 mRNA was rhythmic (peaking during the late night) and was regulated by the circadian clock component REV-ERBα. Finally, the induction of clock genes in both the early and late subjective night was affected by the loss of Cav1.2, with reductions in Per2 and Per1 in the early and late night, respectively. In sum, these results reveal a role of the L-type VGCC Cav1.2 in mediating both clock gene expression and phase advances in response to a light pulse in the late night.
    Full-text Article · Aug 2014 · Journal of Biological Rhythms
  • Source
    Anna Schnell · Sylvie Chappuis · Isabelle Schmutz · [...] · Urs Albrecht
    [Show abstract] [Hide abstract] ABSTRACT: The function of the nuclear receptor Rev-erbα (Nr1d1) in the brain is, apart from its role in the circadian clock mechanism, unknown. Therefore, we compared gene expression profiles in the brain between wild-type and Rev-erbα knock-out (KO) animals. We identified fatty acid binding protein 7 (Fabp7, Blbp) as a direct target of repression by REV-ERBα. Loss of Rev-erbα manifested in memory and mood related behavioral phenotypes and led to overexpression of Fabp7 in various brain areas including the subgranular zone (SGZ) of the hippocampus, where neuronal progenitor cells (NPCs) can initiate adult neurogenesis. We found increased proliferation of hippocampal neurons and loss of its diurnal pattern in Rev-erbα KO mice. In vitro, proliferation and migration of glioblastoma cells were affected by manipulating either Fabp7 expression or REV-ERBα activity. These results suggest an important role of Rev-erbα and Fabp7 in adult neurogenesis, which may open new avenues for treatment of gliomas as well as neurological diseases such as depression and Alzheimer.
    Full-text Article · Jun 2014 · PLoS ONE
  • Source
    Dataset: Carvas2012
    [Show abstract] [Hide abstract] ABSTRACT: Period2 (Per2) is an important component of the circadian clock. Mutation of this gene is associated with vascular endothelial dysfunction and altered glucose metabolism. The aim of this study is to further characterize whole body glucose homeostasis and endothelial nitric oxide (NO) production in response to insulin in the mPer2(Brdm1) mice. We show that mPer2(Brdm1) mice exhibit compromised insulin receptor activation and Akt signaling in various tissues including liver, fat, heart, and aortas with a tissue-specific heterogeneous diurnal pattern, and decreased insulin-stimulated NO release in the aortas in both active and inactive phases of the animals. As compared to wild type (WT) mice, the mPer2(Brdm1) mice reveal hyperinsulinemia, hypoglycemia with lower fasting hepatic glycogen content and glycogen synthase level, no difference in glucose tolerance and insulin tolerance. The mPer2(Brdm1) mice do not show increased predisposition to obesity either on normal chow or high fat diet compared to WT controls. Thus, mice with Per2 gene mutation show altered glucose homeostasis and compromised insulin-stimulated NO release, independently of obesity.
    Full-text Dataset · Dec 2012
  • Source
    [Show abstract] [Hide abstract] ABSTRACT: Period2 (Per2) is an important component of the circadian clock. Mutation of this gene is associated with vascular endothelial dysfunction and altered glucose metabolism. The aim of this study is to further characterize whole body glucose homeostasis and endothelial nitric oxide (NO) production in response to insulin in the mPer2(Brdm1) mice. We show that mPer2(Brdm1) mice exhibit compromised insulin receptor activation and Akt signaling in various tissues including liver, fat, heart, and aortas with a tissue-specific heterogeneous diurnal pattern, and decreased insulin-stimulated NO release in the aortas in both active and inactive phases of the animals. As compared to wild type (WT) mice, the mPer2(Brdm1) mice reveal hyperinsulinemia, hypoglycemia with lower fasting hepatic glycogen content and glycogen synthase level, no difference in glucose tolerance and insulin tolerance. The mPer2(Brdm1) mice do not show increased predisposition to obesity either on normal chow or high fat diet compared to WT controls. Thus, mice with Per2 gene mutation show altered glucose homeostasis and compromised insulin-stimulated NO release, independently of obesity.
    Full-text Article · Aug 2012 · Frontiers in Physiology
  • Source
    Dataset: Figure S2
    Isabelle Schmutz · Sabrina Wendt · Anna Schnell · [...] · Urs Albrecht
    [Show abstract] [Hide abstract] ABSTRACT: NIPP1* expression in the brain has minor effects on the circadian free-running period length. Average period length of control mice and NIPP1* mutants in constant darkness under off dox, on dox and on/off dox conditions. Data are presented as mean ± SEM. (TIF)
    Full-text Dataset · Jun 2011
  • Source
    Dataset: Figure S4
    Isabelle Schmutz · Sabrina Wendt · Anna Schnell · [...] · Urs Albrecht
    [Show abstract] [Hide abstract] ABSTRACT: PER2 expression in the SCN of control and I-1* mutant mice. (A) Immunohistochemical analysis of PER2 in the SCN of control and I-1* mutant mice under on dox conditions. Animals maintained in a LD 12∶12 h cycle were sacrificed every 6 hours. Representative micrographs are shown. The location of each section was determined by Hoechst dye staining. Scale bar 200 µm. (B) Immunohistochemical analysis of PER2 in the SCN at ZT2 at a higher magnification (×40). The top panels show the aPER2 staining, the middle panels the Hoechst dye staining and the lower panels represent the merge of the two stainings. Scale bar 20 µm. (C) Quantitative representation of subcellular localization of PER2 in the SCN at ZT2 in control and I-1* mutant mice. The quantification shows the percentage of cells showing nuclear (N), nuclear and cytoplasmic (N/C) and cytoplasmic PER2 staining. The quantification includes data from 5 SCN sections (approximately 80 nuclei/ section) for each genotype. (TIF)
    Full-text Dataset · Jun 2011
  • Source
    Dataset: Table S2
    Isabelle Schmutz · Sabrina Wendt · Anna Schnell · [...] · Urs Albrecht
    [Show abstract] [Hide abstract] ABSTRACT: Period length of control and I-1* mutant mice. (DOC)
    Full-text Dataset · Jun 2011
  • Source
    Dataset: Figure S1
    Isabelle Schmutz · Sabrina Wendt · Anna Schnell · [...] · Urs Albrecht
    [Show abstract] [Hide abstract] ABSTRACT: Controls of knock-down experiments. (A) Knock-down efficiency of transduced RNAi constructs in U-2 OS cells. Expression levels of the indicated PP1 subunit (PPP1CA, PPP1CB, or PPP1CC) in cells transduced with the non-silencing construct were set to 1. (B) Average period length of Bmal1 luc oscillations in U-2 OS cells not transduced (medium) or transduced with a construct containing scrambled RNAi (non-silencing control) or antisense constructs against the catalytic subunits of PP1, respectively. Period length was determined in three independent experiments (with n = 2–3 cultures). For PPP1CB and PPP1CC two different antisense constructs were used. *** p<0.001, * p<0.05 indicating significance (1-way Anova). The oligo-ID's for the corresponding antisense constructs are indicated in table S1. (TIF)
    Full-text Dataset · Jun 2011
  • Source
    Dataset: Figure S5
    Isabelle Schmutz · Sabrina Wendt · Anna Schnell · [...] · Urs Albrecht
    [Show abstract] [Hide abstract] ABSTRACT: HA-NIPP1* expression alters the subcellular localization of PER2-GFP in NG108-15 cells. (A) Representative micrographs of cells transfected with expression vectors for PER2-GFP and HA-NIPP1*. Shown is the GFP fluorescence (green, left panel), the Hoechst-stain fluorescence (blue, middle panel) and the merge of the two images (right panel). (B) Quantitative representation of the subcellular localization of PER2-GFP expression in NG-108-15 cells. (C) Quantitative representation of the subcellular localization of beta-Catenin-GFP expression. NG108-15 cells were transfected with an expression vector for beta-Catenin-GFP together with either empty pSCT1 expression vector, pSCT1-HA-I-1*, or pSCT1-HA-NIPP1*. GFP positive cells were scored for predominantly nuclear, nuclear and cytoplasmic and predominantly cytoplasmic expression. The relative distribution was determined blinded in three independent experiments (out of 80 GFP-positive cells each). Data are represented as mean + SD. (TIF)
    Full-text Dataset · Jun 2011
  • Source
    Dataset: Figure S3
    Isabelle Schmutz · Sabrina Wendt · Anna Schnell · [...] · Urs Albrecht
    [Show abstract] [Hide abstract] ABSTRACT: Light inducibility of Per1 and Per2 is similar in control and I-1* mutant mice. (A) Induction of Per1 expression in the SCN by a 15-min light pulse applied at CT14 as revealed by in situ hybridization. (B) Induction of Per2 expression by a 15-min light pulse applied at CT14. (C) Induction of Per1 expression by a 15-min light pulse applied at CT22. (D) Induction of Per2 expression by a 15-min light pulse applied at CT22. Light treated and control animals were sacrificed at CT15 or CT23, respectively. The left panels show representative micrographs. The location within the SCN of each section was determined by Hoechst dye staining (blue). The in situ hybridization signal is given in yellow. The quantifications show means ± SEM of normalized optical densities. All experiments were performed with animals under doxycycline treatment (n = 2–4). Scale bar 200 µm. (TIF)
    Full-text Dataset · Jun 2011
  • Source
    Dataset: Table S1
    Isabelle Schmutz · Sabrina Wendt · Anna Schnell · [...] · Urs Albrecht
    [Show abstract] [Hide abstract] ABSTRACT: Antisense constructs. (DOC)
    Full-text Dataset · Jun 2011
  • Source
    Dataset: Figure S6
    Isabelle Schmutz · Sabrina Wendt · Anna Schnell · [...] · Urs Albrecht
    [Show abstract] [Hide abstract] ABSTRACT: Cycloheximide treatment. (A) NG-108-15 cells transiently expressing Per2-V5 either alone or together with HA-I-1* or HA-NIPP1* were treated for up to 4 hours with 25 µg/ml cycloheximide. Samples were analyzed by immunoblotting using the indicated antibodies. (B) Two individual experiments were quantified using the Quantity One 1-D analysis software (Biorad). For each time point, the amount of PER2-V5 was normalized to actin. For each experiment, the normalized amount of PER2-V5 at time point 0 was set to 100%. (TIF)
    Full-text Dataset · Jun 2011
  • Source
    Isabelle Schmutz · Sabrina Wendt · Anna Schnell · [...] · Urs Albrecht
    [Show abstract] [Hide abstract] ABSTRACT: Circadian clocks coordinate the timing of important biological processes. Interconnected transcriptional and post-translational feedback loops based on a set of clock genes generate and maintain these rhythms with a period of about 24 hours. Many clock proteins undergo circadian cycles of post-translational modifications. Among these modifications, protein phosphorylation plays an important role in regulating activity, stability and intracellular localization of clock components. Several protein kinases were characterized as regulators of the circadian clock. However, the function of protein phosphatases, which balance phosphorylation events, in the mammalian clock mechanism is less well understood. Here, we identify protein phosphatase 1 (PP1) as regulator of period and light-induced resetting of the mammalian circadian clock. Down-regulation of PP1 activity in cells by RNA interference and in vivo by expression of a specific inhibitor in the brain of mice tended to lengthen circadian period. Moreover, reduction of PP1 activity in the brain altered light-mediated clock resetting behavior in mice, enhancing the phase shifts in either direction. At the molecular level, diminished PP1 activity increased nuclear accumulation of the clock component PER2 in neurons. Hence, PP1, may reduce PER2 phosphorylation thereby influencing nuclear localization of this protein. This may at least partially influence period and phase shifting properties of the mammalian circadian clock.
    Full-text Article · Jun 2011 · PLoS ONE
  • Source
    I Schmutz · U Albrecht · JA Ripperger
    [Show abstract] [Hide abstract] ABSTRACT: The liver is the important organ to maintain energy homeostasis of an organism. To achieve this, many biochemical reactions run in this organ in a rhythmic fashion. An elegant way to coordinate the temporal expression of genes for metabolic enzymes relies in the link to the circadian timing system. In this fashion not only a maximum of synchronization is achieved, but also anticipation of daily recurring events is possible. Here we will focus on the input and output pathways of the hepatic circadian oscillator and discuss the recently found flexibility of its circadian transcriptional networks.
    Full-text Article · Jun 2011 · Molecular and Cellular Endocrinology
  • Source
    [Show abstract] [Hide abstract] ABSTRACT: Daily patterns of animal behavior are potentially of vast functional importance. Fitness benefits have been identified in nature by the association between individual timing and survival or by the fate of individuals after experimental deletion of their circadian pacemaker. The recent advances in unraveling the molecular basis of circadian timing enable new approaches to natural selection on timing. The investigators report on the effect and fate of the mutant Per2(Brdm1) allele in 4 replicate populations of house mice in a seminatural outside environment over 2 years. This allele is known to compromise circadian organization and entrainment and to cause multiple physiological disturbances. Mice (N=250) bred from Per2(Brdm1) heterozygotes were implanted subcutaneously with transponders and released in approximately Mendelian ratios in four 400 m(2) pens. An electronic system stored the times of all visits to feeders of each individual. The study first demonstrates that mice are not explicitly nocturnal in this natural environment. Feeding activity was predominantly and sometimes exclusively diurnal and spread nearly equally over day and night under the protective snow cover in winter. The effect of Per2(Brdm1) on activity timing is negligible compared to seasonal changes in all genotypes. Second, the Per2(Brdm1) allele did not have persistent negative effects on fitness. In the first year, the allele gradually became less frequent by reducing survival. New cohorts captured had the same Per2(Brdm1) frequency as the survivors from previous cohorts, consistent with an absence of an effect on reproduction. In the second year, the allele recovered to about its initial frequency (0.54). These changes in selective advantage were primarily due to female mice, as females lived longer and the sex ratio dropped to about 25% males in the population. While it is unknown which selective advantage led to the recovery, the results caution against inferences from laboratory experiments on fitness consequences in the natural environment. It also demonstrates that the activity of mice, while strictly nocturnal in the laboratory, may be partially or completely diurnal in the field. The new method allows assessment of natural selection on specific alleles on a day-today basis.
    Full-text Article · Apr 2011 · Journal of Biological Rhythms
  • Dataset: Figure S1
    [Show abstract] [Hide abstract] ABSTRACT: Data on osteocalcin levels at different times (ZT00, ZT06, ZT12 and ZT18) in serum of wildtype, Per2Brdm1, Cry2−/−, and Per2Brdm1/Cry2−/− mice were subjected to COSINOR analysis. There was no statistical difference in the mesor, acrophase or amplitude of the osteocalcin profiles. (0.12 MB PDF)
    Dataset · Jul 2010
  • Dataset: Figure S3
    [Show abstract] [Hide abstract] ABSTRACT: The vertebrae of male mice were prepared as described in Materials and Methods of the main text. The BV/TV-value of the 12 week old male Per2Brdm1 was significantly higher than that of wildtype littermates (p≤0.05, Student's t-test). (0.00 MB PDF)
    Dataset · Jul 2010
  • Source
    [Show abstract] [Hide abstract] ABSTRACT: Clock genes and their protein products regulate circadian rhythms in mammals but have also been implicated in various physiological processes, including bone formation. Osteoblasts build new mineralized bone whereas osteoclasts degrade it thereby balancing bone formation. To evaluate the contribution of clock components in this process, we investigated mice mutant in clock genes for a bone volume phenotype. We found that Per2(Brdm1) mutant mice as well as mice lacking Cry2(-/-) displayed significantly increased bone volume at 12 weeks of age, when bone turnover is high. Per2(Brdm1) mutant mice showed alterations in parameters specific for osteoblasts whereas mice lacking Cry2(-/-) displayed changes in osteoclast specific parameters. Interestingly, inactivation of both Per2 and Cry2 genes leads to normal bone volume as observed in wild type animals. Importantly, osteoclast parameters affected due to the lack of Cry2, remained at the level seen in the Cry2(-/-) mutants despite the simultaneous inactivation of Per2. This indicates that Cry2 and Per2 affect distinct pathways in the regulation of bone volume with Cry2 influencing mostly the osteoclastic cellular component of bone and Per2 acting on osteoblast parameters.
    Full-text Article · Jul 2010 · PLoS ONE
  • Dataset: Figure S4
    [Show abstract] [Hide abstract] ABSTRACT: The tibiae of female mice were prepared as described in Materials and Methods of the main text. The BV/TV-value of the 12 week old female Cry2−/− mice was significantly higher than that of wildtype littermates (p≤0.01, ANOVA with Bonferroni post-test). Wildtype and Per2Brdm1/Cry2−/− mice were not statistically different. (0.00 MB PDF)
    Dataset · Jul 2010
  • Dataset: Figure S7
    [Show abstract] [Hide abstract] ABSTRACT: Intact parathyroid hormone (iPTH) levels in plasma at ZT04 (four hours after lights on) were determined by the mouse intact PTH ELISA kit (Immutopics, San Clemente, CA, USA). Intact PTH levels were significantly higher in plasma from Per2Brdm1 compared to wildtype (p≤0.01, Student's t-test). (0.00 MB PDF)
    Dataset · Jul 2010