Publications by authors named "Catharina E E M Van der Zee"

22 Publications

  • Page 1 of 1

Haploinsufficiency of EHMT1 improves pattern separation and increases hippocampal cell proliferation.

Sci Rep 2017 01 10;7:40284. Epub 2017 Jan 10.

Department of Cognitive Neuroscience, Radboudumc, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands.

Heterozygous mutations or deletions of the human Euchromatin Histone Methyltransferase 1 (EHMT1) gene are the main causes of Kleefstra syndrome, a neurodevelopmental disorder that is characterized by impaired memory, autistic features and mostly severe intellectual disability. Previously, Ehmt1 heterozygous knockout mice were found to exhibit cranial abnormalities and decreased sociability, phenotypes similar to those observed in Kleefstra syndrome patients. In addition, Ehmt1 knockout mice were impaired at fear extinction and novel- and spatial object recognition. In this study, Ehmt1 and wild-type mice were tested on several cognitive tests in a touchscreen-equipped operant chamber to further investigate the nature of learning and memory changes. Performance of Ehmt1 mice in the Visual Discrimination &Reversal learning, object-location Paired-Associates learning- and Extinction learning tasks was found to be unimpaired. Remarkably, Ehmt1 mice showed enhanced performance on the Location Discrimination test of pattern separation. In line with improved Location Discrimination ability, an increase in BrdU-labelled cells in the subgranular zone of the dentate gyrus was observed. In conclusion, reduced levels of EHMT1 protein in Ehmt1 mice does not result in general learning deficits in a touchscreen-based battery, but leads to increased adult cell proliferation in the hippocampus and enhanced pattern separation ability.
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http://dx.doi.org/10.1038/srep40284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5223204PMC
January 2017

Actual drawing of histological images improves knowledge retention.

Anat Sci Educ 2016 Jan-Feb;9(1):60-70. Epub 2015 May 29.

Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

Medical students have to process a large amount of information during the first years of their study, which has to be retained over long periods of nonuse. Therefore, it would be beneficial when knowledge is gained in a way that promotes long-term retention. Paper-and-pencil drawings for the uptake of form-function relationships of basic tissues has been a teaching tool for a long time, but now seems to be redundant with virtual microscopy on computer-screens and printers everywhere. Several studies claimed that, apart from learning from pictures, actual drawing of images significantly improved knowledge retention. However, these studies applied only immediate post-tests. We investigated the effects of actual drawing of histological images, using randomized cross-over design and different retention periods. The first part of the study concerned esophageal and tracheal epithelium, with 384 medical and biomedical sciences students randomly assigned to either the drawing or the nondrawing group. For the second part of the study, concerning heart muscle cells, students from the previous drawing group were now assigned to the nondrawing group and vice versa. One, four, and six weeks after the experimental intervention, the students were given a free recall test and a questionnaire or drawing exercise, to determine the amount of knowledge retention. The data from this study showed that knowledge retention was significantly improved in the drawing groups compared with the nondrawing groups, even after four or six weeks. This suggests that actual drawing of histological images can be used as a tool to improve long-term knowledge retention.
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http://dx.doi.org/10.1002/ase.1545DOI Listing
October 2016

Protein tyrosine phosphatase receptor type R deficient mice exhibit increased exploration in a new environment and impaired novel object recognition memory.

Behav Brain Res 2014 May 18;265:111-20. Epub 2014 Feb 18.

Department of Cell Biology, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Electronic address:

Mouse gene Ptprr encodes multiple protein tyrosine phosphatase receptor type R (PTPRR) isoforms that negatively regulate mitogen-activated protein kinase (MAPK) signaling pathways. In the mouse brain, PTPRR proteins are expressed in cerebellum, olfactory bulb, hippocampus, amygdala and perirhinal cortex but their precise role in these regions remains to be determined. Here, we evaluated phenotypic consequences of loss of PTPRR activity and found that basal smell was normal for Ptprr(-/-) mice. Also, spatial learning and fear-associated contextual learning were unaffected. PTPRR deficiency, however, resulted in impaired novel object recognition and a striking increase in exploratory activity in a new environment. The data corroborate the importance of proper control of MAPK signaling in cerebral functions and put forward PTPRR as a novel target to modulate synaptic processes.
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http://dx.doi.org/10.1016/j.bbr.2014.02.014DOI Listing
May 2014

Reduced Euchromatin histone methyltransferase 1 causes developmental delay, hypotonia, and cranial abnormalities associated with increased bone gene expression in Kleefstra syndrome mice.

Dev Biol 2014 Feb 19;386(2):395-407. Epub 2013 Dec 19.

Department of Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands; Department of Cognitive Neurosciences, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands.

Haploinsufficiency of Euchromatin histone methyltransferase 1 (EHMT1), a chromatin modifying enzyme, is the cause of Kleefstra syndrome (KS). KS is an intellectual disability (ID) syndrome, with general developmental delay, hypotonia, and craniofacial dysmorphisms as additional core features. Recent studies have been focused on the role of EHMT1 in learning and memory, linked to the ID phenotype of KS patients. In this study we used the Ehmt1(+/-) mouse model, and investigated whether the core features of KS were mimicked in these mice. When comparing Ehmt1(+/-) mice to wildtype littermates we observed delayed postnatal growth, eye opening, ear opening, and upper incisor eruption, indicating a delayed postnatal development. Furthermore, tests for muscular strength and motor coordination showed features of hypotonia in young Ehmt1(+/-) mice. Lastly, we found that Ehmt1(+/-) mice showed brachycephalic crania, a shorter or bent nose, and hypertelorism, reminiscent of the craniofacial dysmorphisms seen in KS. In addition, gene expression analysis revealed a significant upregulation of the mRNA levels of Runx2 and several other bone tissue related genes in P28 Ehmt1(+/-) mice. Runx2 immunostaining also appeared to be increased. The mRNA upregulation was associated with decreased histone H3 lysine 9 dimethylation (H3K9me2) levels, the epigenetic mark deposited by Ehmt1, in the promoter region of these genes. Together, Ehmt1(+/-) mice indeed recapitulate KS core features and can be used as an animal model for Kleefstra syndrome. The increased expression of bone developmental genes in the Ehmt1(+/-) mice likely contributes to their cranial dysmorphisms and might be explained by diminished Ehmt1-induced H3K9 dimethylation.
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http://dx.doi.org/10.1016/j.ydbio.2013.12.016DOI Listing
February 2014

Hypothalamic plasticity of neuropeptide Y is lacking in brain-type creatine kinase double knockout mice with defective thermoregulation.

Eur J Pharmacol 2013 Nov 25;719(1-3):137-144. Epub 2013 Jul 25.

Department of Cell Biology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Electronic address:

The neural substrate of adaptive thermoregulation in mice lacking both brain-type creatine kinase isoforms is further investigated. The cytosolic brain-type creatine kinase (CK-B) and mitochondrial ubiquitous creatine kinase (UbCKmit) are expressed in neural cells throughout the central and peripheral nervous system, where they have an important role in cellular energy homeostasis. Several integral functions appear altered when creatine kinases are absent in the brain (Jost et al., 2002; Streijger et al., 2004, 2005), which has been explained by inefficient neuronal transmission. The CK--/-- double knockout mice demonstrate every morning a body temperature drop of ~1.0 °C, and they have impaired thermogenesis, as revealed by severe hypothermia upon cold exposure. This defective thermoregulation is not associated with abnormal food intake, decreased locomotive activity, or increased torpor sensitivity. Although white and brown adipose tissue fat pads are diminished in CK--/-- mice, intravenous norepinephrine infusion results in a normal brown adipose tissue response with increasing core body temperatures, indicating that the sympathetic innervation functions correctly (Streijger et al., 2009). This study revealed c-fos changes following a cold challenge, and that neuropeptide Y levels were decreased in the paraventricular nucleus of wildtype, but not CK--/--, mice. A reduction in hypothalamic neuropeptide Y is coupled to increased uncoupling protein 1 expression in brown adipose tissue, resulting in thermogenesis. In CK--/-- mice the neuropeptide Y levels did not change. This lack of hypothalamic plasticity of neuropeptide Y might be the result of inefficient neuronal transmission or can be explained by the previous observation of reduced circulating levels of leptin in CK--/-- mice.
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http://dx.doi.org/10.1016/j.ejphar.2013.07.027DOI Listing
November 2013

Hippocampal dysfunction in the Euchromatin histone methyltransferase 1 heterozygous knockout mouse model for Kleefstra syndrome.

Hum Mol Genet 2013 Mar 21;22(5):852-66. Epub 2012 Nov 21.

Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Nijmegen, the Netherlands.

Euchromatin histone methyltransferase 1 (EHMT1) is a highly conserved protein that catalyzes mono- and dimethylation of histone H3 lysine 9, thereby epigenetically regulating transcription. Kleefstra syndrome (KS), is caused by haploinsufficiency of the EHMT1 gene, and is an example of an emerging group of intellectual disability (ID) disorders caused by genes encoding epigenetic regulators of neuronal gene activity. Little is known about the mechanisms underlying this disorder, prompting us to study the Euchromatin histone methyltransferase 1 heterozygous knockout (Ehmt1(+/-)) mice as a model for KS. In agreement with the cognitive disturbances observed in patients with KS, we detected deficits in fear extinction learning and both novel and spatial object recognition in Ehmt1(+/-) mice. These learning and memory deficits were associated with a significant reduction in dendritic arborization and the number of mature spines in hippocampal CA1 pyramidal neurons of Ehmt1(+/-) mice. In-depth analysis of the electrophysiological properties of CA3-CA1 synapses revealed no differences in basal synaptic transmission or theta-burst induced long-term potentiation (LTP). However, paired-pulse facilitation (PPF) was significantly increased in Ehmt1(+/-) neurons, pointing to a potential deficiency in presynaptic neurotransmitter release. Accordingly, a reduction in the frequency of miniature excitatory post-synaptic currents (mEPSCs) was observed in Ehmt1(+/-) neurons. These data demonstrate that Ehmt1 haploinsufficiency in mice leads to learning deficits and synaptic dysfunction, providing a possible mechanism for the ID phenotype in patients with KS.
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http://dx.doi.org/10.1093/hmg/dds490DOI Listing
March 2013

Enoxaparin treatment administered at both early and late stages of amyloid β deposition improves cognition of APPswe/PS1dE9 mice with differential effects on brain Aβ levels.

Neurobiol Dis 2010 Oct 22;40(1):340-7. Epub 2010 Jun 22.

Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Alzheimer Centre Nijmegen, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

Enoxaparin (Enox), a low molecular weight heparin, has been shown to lower brain amyloid beta (A beta) load in a mouse model for Alzheimer's disease. However, the effect of Enox on cognition was not studied. Therefore, we examined the effect of peripheral Enox treatment on cognition and brain A beta levels in the APPswe/PS1dE9 mouse model by giving injections at an early (starting at 5 months of age) and late (starting at 10 and 12 months of age) stage of A beta accumulation for 3 months. Although Enox had no effect on behaviour in the open field at any age, it improved spatial memory in the Morris water maze in 5-, 10- and 12-month-old mice. Furthermore, Enox treatment seemed to decrease guanidine HCl-extracted brain A beta levels at 5 months of age, but significantly increased guanidine HCl-extracted A beta 42 and A beta 40 levels in both 10- and 12-month-old mice. In vitro, Enox increased aggregation of A beta, even when A beta was pre-aggregated. In conclusion, Enox treatment, either at an early or a late stage of A beta accumulation, could improve cognition in APPswe/PS1dE9 mice. However, since Enox treatment at an early stage of A beta accumulation decreased guanidine HCl-extracted A beta levels and Enox treatment at a late stage enhanced guanidine HCl-extracted A beta levels, it seems that Enox influences A beta deposition differently at different stages of A beta pathology. In any case, our study suggests that enoxaparin treatment has potential as a therapeutic agent for Alzheimer's disease.
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http://dx.doi.org/10.1016/j.nbd.2010.06.008DOI Listing
October 2010

Flow of energy in the outer retina in darkness and in light.

Proc Natl Acad Sci U S A 2010 May 5;107(19):8599-604. Epub 2010 May 5.

Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.

Structural features of neurons create challenges for effective production and distribution of essential metabolic energy. We investigated how metabolic energy is distributed between cellular compartments in photoreceptors. In avascular retinas, aerobic production of energy occurs only in mitochondria that are located centrally within the photoreceptor. Our findings indicate that metabolic energy flows from these central mitochondria as phosphocreatine toward the photoreceptor's synaptic terminal in darkness. In light, it flows in the opposite direction as ATP toward the outer segment. Consistent with this model, inhibition of creatine kinase in avascular retinas blocks synaptic transmission without influencing outer segment activity. Our findings also reveal how vascularization of neuronal tissue can influence the strategies neurons use for energy management. In vascularized retinas, mitochondria in the synaptic terminals of photoreceptors make neurotransmission less dependent on creatine kinase. Thus, vasculature of the tissue and the intracellular distribution of mitochondria can play key roles in setting the strategy for energy distribution in neurons.
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http://dx.doi.org/10.1073/pnas.1002471107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2889335PMC
May 2010

The lysosomal trafficking regulator interacting protein-5 localizes mainly in epithelial cells.

J Mol Histol 2010 Feb 1;41(1):61-74. Epub 2010 Apr 1.

Department of Physiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

Endocytosis, subsequent protein sorting into multivesicular bodies (MVBs), and eventual degradation in lysosomes compose an important mechanism for controlling protein expression on the plasma membrane. The lysosomal trafficking regulator interacting protein-5 (LIP5) is part of the complex protein machinery involved in MVB biosynthesis. LIP5 interacts with other players of the ESCRT machinery as well as with two known cargo proteins, AQP2 and EGFR, whose degradation is affected upon reduction of LIP5 expression. To investigate the expression and localization pattern of LIP5, we studied LIP5 protein expression in a mouse tissue panel and subjected various rodent and human tissues to immunohistochemistry. Immunoblotting revealed that, except for jejunum, LIP5 is expressed as a 42 kDa protein in all mouse tissues tested. Alternatively-spliced gene products could not be detected. Immunohistochemical studies revealed that in tissues positive for LIP5, LIP5 is detected in virtually all epithelial cells of the examined rodent and human tissues. The observed LIP5 expression in epithelial tissues suggests that LIP5 is of particular importance in the MVB sorting and degradation of proteins expressed in polarized cells.
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http://dx.doi.org/10.1007/s10735-010-9263-9DOI Listing
February 2010

Reduced exploration, increased anxiety, and altered social behavior: Autistic-like features of euchromatin histone methyltransferase 1 heterozygous knockout mice.

Behav Brain Res 2010 Mar 5;208(1):47-55. Epub 2009 Nov 5.

Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.

The 9q34.3 subtelomeric deletion syndrome is a newly defined mental retardation syndrome, caused by haplo-insufficiency of the euchromatin histone methyltransferase 1 (EHMT1) gene. Patients also have childhood hypotonia, facial dysmorphisms, delay in reaching developmental milestones, and behavioral problems like aggressive outbursts, hypoactivity, or autistic-like features. Male and female heterozygous Ehmt1 knockout mice (Ehmt1(+/-), aged 1-20 months, kept on a C57BL/6J background), were used to investigate whether they mimic the patients behavioral characteristics by comparing their behavior to wildtype littermates. The Ehmt1(+/-) mice revealed reduced activity and exploration, with increased anxiety compared to wildtype mice when exposed to novel environments in the open field, object exploration, marble burying, light-dark box, mirrored chamber and T-maze tests. They also demonstrated diminished social play when encountering a mouse from a different litter, and a delayed or absent response to social novelty when exposed to a stranger mouse. However, no differences in phenotyper home cage locomotor activity or rotarod motor function were observed between Ehmt1(+/-) and wildtype mice. Together, these results indicate that the hypoactivity and the autistic-like features of 9q34.3 subtelomeric deletion syndrome patients are recapitulated in this Ehmt1(+/-) mouse model, and that the hypoactivity is apparently not caused by any motor dysfunction. Together, these observations make it plausible that the Ehmt1(+/-) mouse is a faithful mammalian model for the autistic-like behavioral features of patients with the 9q34.3 subtelomeric deletion syndrome.
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http://dx.doi.org/10.1016/j.bbr.2009.11.008DOI Listing
March 2010

Complete brain-type creatine kinase deficiency in mice blocks seizure activity and affects intracellular calcium kinetics.

Epilepsia 2010 Jan 14;51(1):79-88. Epub 2009 Jul 14.

Department of Cell Biology, NCMLS, Radboud University Nijmegen Medical Centre, Nijmegen, Nijmegen, The Netherlands.

Purpose: Brain-type creatine kinase (CK-B) and ubiquitous mitochondrial creatine kinase (UbCKmit) act as components of local phosphocreatine ATP shuttles that help in the compartmentalization and maintenance of pools of high-energy phosphate molecules in both neurons and glial cells. We investigated the role of these brain-type creatine kinases during extreme energy-demanding conditions in vivo (generalized tonic-clonic seizures) and in vitro.

Methods: The physiologic response of wild-types and mice lacking both CK-B and UbCKmit (CK--/--mice) to pentylenetetrazole (PTZ)-induced seizures was measured using electroencephalography (EEG) recordings and behavioral monitoring. In vitro intracellular Ca(2+) kinetics in hippocampal granule neurons were monitored upon single and repetitive depolarizations.

Results: PTZ induced in only a few CK--/-- mice PTZ seizure-like behavior, but in all wild-types a full-blown seizure. EEG analysis showed that preseizure jerking was associated with high-amplitude discharges. Wild-type EEG recordings showed continuous runs of rhythmic 4-6 Hz activity, whereas no rhythmic EEG activities were observed in the few CK--/-- mice that developed a behavioral seizure. All other CK--/-- mice displayed a sudden postictal depression without any development of a generalized seizure. Hippocampal granule neurons of CK--/-- mice displayed a higher Ca(2+) removal speed following repetitive KCl-induced depolarizations.

Discussion: Deficiency for creatine kinase is affecting brain energy metabolism and will likely contribute to the disturbance of seizure development. Because CK--/-- hippocampal neurons exhibited an increase in Ca(2+) removal rate of elevated intracellular levels, we conclude that altered Ca(2+) clearance in CK--/-- neurons could play a role in the abnormal EEG and seizure activity.
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http://dx.doi.org/10.1111/j.1528-1167.2009.02182.xDOI Listing
January 2010

Mice lacking brain-type creatine kinase activity show defective thermoregulation.

Physiol Behav 2009 Apr 10;97(1):76-86. Epub 2009 Feb 10.

Department of Cell Biology, NCMLS, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

The cytosolic brain-type creatine kinase and mitochondrial ubiquitous creatine kinase (CK-B and UbCKmit) are expressed during the prepubescent and adult period of mammalian life. These creatine kinase (CK) isoforms are present in neural cell types throughout the central and peripheral nervous system and in smooth muscle containing tissues, where they have an important role in cellular energy homeostasis. Here, we report on the coupling of CK activity to body temperature rhythm and adaptive thermoregulation in mice. With both brain-type CK isoforms being absent, the body temperature reproducibly drops ~1.0 degrees C below normal during every morning (inactive) period in the daily cycle. Facultative non-shivering thermogenesis is also impaired, since CK--/-- mice develop severe hypothermia during 24 h cold exposure. A relationship with fat metabolism was suggested because comparison of CK--/-- mice with wildtype controls revealed decreased weight gain associated with less white and brown fat accumulation and smaller brown adipocytes. Also, circulating levels of glucose, triglycerides and leptin are reduced. Extensive physiological testing and uncoupling protein1 analysis showed, however, that the thermogenic problems are not due to abnormal responsiveness of brown adipocytes, since noradrenaline infusion produced a normal increase of body temperature. Moreover, we demonstrate that the cyclic drop in morning temperature is also not related to altered rhythmicity with reduced locomotion, diminished food intake or increased torpor sensitivity. Although several integral functions appear altered when CK is absent in the brain, combined findings point into the direction of inefficient neuronal transmission as the dominant factor in the thermoregulatory defect.
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http://dx.doi.org/10.1016/j.physbeh.2009.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3133955PMC
April 2009

Conditional deletion of the Itgb4 integrin gene in Schwann cells leads to delayed peripheral nerve regeneration.

J Neurosci 2008 Oct;28(44):11292-303

Department of Cell Biology, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Center Nijmegen, 6525 GA Nijmegen, The Netherlands.

Several different integrins participate in the complex interactions that promote repair of the peripheral nervous system. The role of the integrin alpha6beta4 in peripheral nerve regeneration was investigated in mice by cre-mediated deletion of the Itgb4 (beta4) gene in Schwann cells. After a crush lesion of the sciatic nerve, the recovery of motor, but not that of sensory, nerve function in beta4(-/-) mice was delayed. Immunostaining of neurofilament-200 showed that there also is a significant reduction in the number of newly outgrowing nerve sprouts in beta4(-/-) mice. Morphometric quantitative measurements revealed that fewer axons are myelinated in the nonlesioned beta4(-/-) nerves. After a sciatic nerve crush lesion, beta4(-/-) mice did not only have fewer myelinated axons compared with lesioned wild-type nerve, but their axons also showed a higher g-ratio and a thinner myelin sheath, pointing at reduced myelination. This study revealed that the beta4 protein remains expressed in the early stages of peripheral regeneration, albeit at levels lower than those before the lesion was inflicted, and showed that laminin deposition is not altered in the absence of beta4. These results together demonstrate that integrin alpha6beta4 plays an essential role in axonal regeneration and subsequent myelination.
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http://dx.doi.org/10.1523/JNEUROSCI.3068-08.2008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6671513PMC
October 2008

Hair bundles are specialized for ATP delivery via creatine kinase.

Neuron 2007 Feb;53(3):371-86

Oregon Hearing Research Center and Vollum Institute, Oregon Health and Science University, Portland, OR 97239, USA.

When stimulated strongly, a hair cell's mechanically sensitive hair bundle may consume ATP too rapidly for replenishment by diffusion. To provide a broad view of the bundle's protein complement, including those proteins participating in energy metabolism, we used shotgun mass spectrometry methods to identify proteins of purified chicken vestibular bundles. In addition to cytoskeletal proteins, proteins involved in Ca(2+) regulation, and stress-response proteins, many of the most abundant bundle proteins that were identified by mass spectrometry were involved in ATP synthesis. After beta-actin, the cytosolic brain isoform of creatine kinase was the next most abundant bundle protein; at approximately 0.5 mM, creatine kinase is capable of maintaining high ATP levels despite 1 mM/s ATP consumption by the plasma-membrane Ca(2+)-ATPase. Consistent with this critical role in hair bundle function, the creatine kinase circuit is essential for high-sensitivity hearing as demonstrated by hearing loss in creatine kinase knockout mice.
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http://dx.doi.org/10.1016/j.neuron.2006.12.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1839076PMC
February 2007

Altered MAP kinase phosphorylation and impaired motor coordination in PTPRR deficient mice.

J Neurochem 2007 May 31;101(3):829-40. Epub 2007 Jan 31.

Department of Cell Biology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

The neuronal protein tyrosine phosphatases encoded by mouse gene Ptprr (PTPBR7, PTP-SL, PTPPBSgamma-42 and PTPPBSgamma-37) have been implicated in mitogen-activated protein (MAP) kinase deactivation on the basis of transfection experiments. To determine their physiological role in vivo, we generated mice that lack all PTPRR isoforms. Ptprr-/- mice were viable and fertile, and not different from wildtype littermates regarding general physiology or explorative behaviour. Highest PTPRR protein levels are in cerebellum Purkinje cells, but no overt effects of PTPRR deficiency on brain morphology, Purkinje cell number or dendritic branching were detected. However, MAP kinase phosphorylation levels were significantly altered in the PTPRR-deficient cerebellum and cerebrum homogenates. Most notably, increased phospho-ERK1/2 immunostaining density was observed in the basal portion and axon hillock of Ptprr-/- Purkinje cells. Concomitantly, Ptprr-/- mice displayed ataxia characterized by defects in fine motor coordination and balance skills. Collectively, these results establish the PTPRR proteins as physiological regulators of MAP kinase signalling cascades in neuronal tissue and demonstrate their involvement in cerebellum motor function.
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http://dx.doi.org/10.1111/j.1471-4159.2006.04398.xDOI Listing
May 2007

Effects of LAR and PTP-BL phosphatase deficiency on adult mouse retinal cells activated by lens injury.

Eur J Neurosci 2005 May;21(9):2375-83

Molecular Neuroscience Group, Department of Medicine, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.

Using intact and lens-lesioned wildtype, leucocyte common antigen-related phosphatase deficient (LARDeltaP) and protein tyrosine phosphatase (PTP)-BAS-like phosphatase deficient (PTP-BLDeltaP) mice, we have evaluated the role of LAR and PTP-BL in retinal ganglion cell survival and neuritogenesis, and survival of activated retinal glia in vitro. There were no differences in in vitro retinal ganglion cell neuritogenesis and survival, as well as in activated retinal glia survival between intact wildtype and intact LARDeltaP or PTP-BLDeltaP mutant mice. In wildtype, LARDeltaP, and PTP-BLDeltaP retinal cultures, pre-conditioning by lens injury significantly increased retinal ganglion cell neuritogenesis and activated retinal glia numbers. However, in retinal cultures from lens-lesioned LARDeltaP and PTP-BLDeltaP mice, significantly smaller percentages of retinal ganglion cells grew neurites compared to lens-lesioned wildtype cultures. Significantly increased numbers of retinal ganglion cells survived in retinal cultures from lens-lesioned LARDeltaP mice compared to lens-lesioned wildtypes. PTP-BL phosphatase deficiency did not affect retinal ganglion cell survival in retinal cultures from lens-lesioned mice, though activated retinal glia numbers were significantly reduced in cultures from lens-lesioned PTP-BLDeltaP mice compared to lens-lesioned wildtypes. In summary, a functional phenotype was found in LARDeltaP and PTP-BLDeltaP mice, that was only obvious in lens lesion-stimulated retinal cultures. These observations suggest that LAR enhances retinal ganglion cell neurite initiation whilst suppressing retinal ganglion cell survival, and that PTP-BL facilitates both retinal ganglion cell neurite initiation and survival of activated retinal glia.
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http://dx.doi.org/10.1111/j.1460-9568.2005.04065.xDOI Listing
May 2005

Structural and behavioural consequences of double deficiency for creatine kinases BCK and UbCKmit.

Behav Brain Res 2005 Feb;157(2):219-34

Department of Cell Biology, NCMLS, UMC Radboud, University of Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.

The cytosolic brain-type creatine kinase (BCK) isoform and the mitochondrial ubiquitous creatine kinase (UbCKmit) isoform are both important for the maintenance and distribution of cellular energy in neurons and astrocytes. Previously, we reported that mice deficient for BCK or UbCKmit each showed a surprisingly mild phenotype, probably due to reciprocal functional compensation by the remaining creatine kinase. This study shows that adult male mice lacking both creatine kinase isoforms (CK--/-- double knockout mice) have a reduced body weight, and demonstrate a severely impaired spatial learning in both a dry and a wet maze, lower nestbuilding activity and diminished acoustic startle reflex responses when compared to age-matched male wildtype mice with the same genetic background. In contrast, their visual and motor functions, exploration behaviour, prepulse inhibition and anxiety-related responses were not changed, suggesting no global deficit in sensorimotor function, hearing or motivation. Morphological analysis of CK--/-- double knockout brains revealed a reduction of approximately 7% in wet brain weight and hippocampal size, a approximately 15% smaller regio-inferior and relatively larger supra-pyramidal, and intra-infra-pyramidal mossy fiber areas. These results suggest that lack of both brain specific creatine kinase isoforms renders the synaptic circuitry in adult brain less efficient in coping with sensory or cognitive activity related challenges.
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http://dx.doi.org/10.1016/j.bbr.2004.07.002DOI Listing
February 2005

Mice lacking leukocyte common antigen-related (LAR) protein tyrosine phosphatase domains demonstrate spatial learning impairment in the two-trial water maze and hyperactivity in multiple behavioural tests.

Behav Brain Res 2004 Sep;154(1):171-82

Department of Cell Biology, Nijmegen Center for Molecular Life Sciences, UMC St. Radboud, University of Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.

Leukocyte common antigen-related (LAR) protein is a cell adhesion molecule-like receptor-type protein tyrosine phosphatase. We previously reported that in LAR tyrosine phosphatase-deficient (LAR-Delta P) mice the number and size of basal forebrain cholinergic neurons as well as their innervation of the hippocampal area was reduced. With the hippocampus being implicated in behavioural activity aspects, including learning and memory processes, we assessed possible phenotypic consequences of LAR phosphatase deficiency using a battery of rodent behaviour tests. Motor function and co-ordination tests as well as spatial learning ability assays did not reveal any performance differences between wildtype and LAR-Delta P mice. A spatial learning impairment was found in the difficult variant of the Morris water maze. Exploration, nestbuilding and activity tests indicated that LAR-Delta P mice were more active than wildtype littermates. The observed hyperactivity in LAR-Delta P mice could not be explained by altered anxiety or curiosity levels, and was found to be persistent throughout the nocturnal period. In conclusion, behavioural testing of the LAR-Delta P mice revealed a spatial learning impairment and a significant increase in activity.
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http://dx.doi.org/10.1016/j.bbr.2004.02.006DOI Listing
September 2004

Mild impairment of motor nerve repair in mice lacking PTP-BL tyrosine phosphatase activity.

Physiol Genomics 2004 Sep 29;19(1):50-60. Epub 2004 Jun 29.

Department of Cell Biology, Nijmegen Center for Molecular Life Sciences, University Medical Center Nijmegen, 6525 GA Nijmegen, The Netherlands.

Mouse PTP-BL is a large, nontransmembrane protein tyrosine phosphatase of unclear physiological function that consists of a KIND domain, a FERM domain, five PDZ domains, and a COOH-terminal catalytic PTP domain. PTP-BL and its human ortholog PTP-BAS have been proposed to play a role in the regulation of microfilament dynamics, cytokinesis, apoptosis, and neurite outgrowth. To investigate the biological function of PTP-BL enzyme activity, we have generated mice that lack the PTP-BL PTP moiety. These PTP-BL(DeltaP/DeltaP) mice are viable and fertile and do not present overt morphological alterations. Although PTP-BL is expressed in most hematopoietic cell lineages, no alterations of thymocyte development in PTP-BL(DeltaP/DeltaP) mice could be detected. Sciatic nerve lesioning revealed that sensory nerve recovery is unaltered in these mice. In contrast, a very mild but significant impairment of motor nerve repair was observed. Our findings exclude an essential role for PTP-BL as a phosphotyrosine phosphatase and rather are in line with a role as scaffolding or anchoring molecule.
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http://dx.doi.org/10.1152/physiolgenomics.00079.2004DOI Listing
September 2004

Mice lacking the UbCKmit isoform of creatine kinase reveal slower spatial learning acquisition, diminished exploration and habituation, and reduced acoustic startle reflex responses.

Mol Cell Biochem 2004 Jan-Feb;256-257(1-2):305-18

Department of Cell Biology NCMLS, University Medical Center (UMC), University of Nijmegen, The Netherlands.

Brain-type creatine kinases B-CK (cytosolic) and UbCKmit (mitochondrial) are considered important for the maintenance and distribution of cellular energy in the central nervous system. Previously, we have demonstrated an abnormal behavioral phenotype in mice lacking the B-CK creatine kinase isoform, regarding exploration, habituation, seizure susceptibility and spatial learning. The phenotype in these mice was associated with histological adaptations in the hippocampal mossy fiber field size. Here, mice lacking the ubiquitous mitochondrial creatine kinase isoform (UbCKmit-/- mice) showed, when subjected to a similar battery of behavioral tasks, diminished open field habituation and slower spatial learning acquisition in the Morris water maze task, but normal sensory or motor functions. A reduced acoustic startle response, higher threshold, and lack of prepulse inhibition were observed in UbCKmit-/- mice, suggesting that the unconditioned reflexive responsiveness is not optimal. Our findings suggest a role for mitochondrial CK-mediated high-energy phosphoryl transfer in synaptic signalling in the acoustic signal response network and hippocampal-dependent learning circuitry of brain. Finally, we demonstrate that UbCKmit has a widespread occurrence in the cell soma of neuronal nuclei along the rostro-caudal axis of the brain, i.e. cortex, midbrain, hindbrain, cerebellum and brainstem, similar to the occurrence of B-CK. This may explain the similarity of phenotypes in mice lacking B-CK or UbCKmit. We predict that the remaining functional intactness of the cytosolic B-CK reaction and perhaps the compensatory role of other phosphoryl transfer systems are sufficient to sustain the energy requirements for basic sensory, motor and physiological activities in UbCKmit-/- mice.
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http://dx.doi.org/10.1023/b:mcbi.0000009877.90129.e3DOI Listing
November 2004

The DMWD protein from the myotonic dystrophy (DM1) gene region is developmentally regulated and is present most prominently in synapse-dense brain areas.

Brain Res 2003 May;971(1):116-27

Department of Cell Biology, NCMLS, UMC Radboud, University of Nijmegen, Geert Grooteplein Zuid 28, 6525 GA, Nijmegen, The Netherlands.

The DMWD gene is located in the myotonic dystrophy (DM1) gene cluster on 19q, just upstream of the DMPK gene. RNA and protein products of this gene are ubiquitously expressed in all adult tissues, but occur most abundant in testes and brain. Altered expression of DMWD mRNA in DM1 patients has been observed, suggesting a role of the DMWD gene products in disease manifestation. Here we focussed on DMWD expression in mouse brain and followed mRNA and protein levels and (intra)cellular location in developing brain in vivo as well as in differentiating neuronal cell cultures in vitro. In the interval between postnatal days P7 and P21, the steady-state level of DMWD mRNA remained constant, whereas the DMWD protein (doublet of 70 kDa) level gradually increased during the same period. The DMWD protein was expressed throughout the brain, at a low level in glial cells, more prominently in neurons and specifically in the neuropil of brain areas with a high density of synaptic connections. Intracellularly, DMWD was dispersed in a punctuate fashion throughout the neural cell body, the nucleus and the dendrites with their synapses, but was excluded from axons. Based on these findings and on new literature data concerning the role of DMWD homologs in lower eukaryotes, we discuss the possible role of DMWD in the brain-related symptoms seen in DM1 patients.
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http://dx.doi.org/10.1016/s0006-8993(03)02430-2DOI Listing
May 2003

Creatine kinase B-driven energy transfer in the brain is important for habituation and spatial learning behaviour, mossy fibre field size and determination of seizure susceptibility.

Eur J Neurosci 2002 May;15(10):1692-706

Department of Cell Biology, University Medical Center St. Radboud, NCMLS, University of Nijmegen, Geert Grooteplein 28, 6525 GA, The Netherlands.

Creatine kinases are important in maintaining cellular-energy homeostasis, and neuroprotective effects have been attributed to the administration of creatine and creatine-like compounds. Herein we examine whether ablation of the cytosolic brain-type creatine kinase (B-CK) in mice has detrimental effects on brain development, physiological integrity or task performance. Mice deficient in B-CK (B-CK-/-) showed no gross abnormalities in brain anatomy or mitochondrial ultrastructure, but had a larger intra- and infrapyramidal mossy fibre area. Nuclear magnetic resonance spectroscopy revealed that adenosine triphosphate (ATP) and phosphocreatine (PCr) levels were unaffected, but demonstrated an apparent reduction of the PCr left arrow over right arrow ATP phosphorus exchange capacity in these mice. When assessing behavioural characteristics B-CK-/- animals showed diminished open-field habituation. In the water maze, adult B-CK-/- mice were slower to learn, but acquired the spatial task. This task performance deficit persisted in 24-month-old, aged B-CK-/- mice, on top of the age-related memory decline normally seen in old animals. Finally, a delayed development of pentylenetetrazole-induced seizures (creating a high-energy demand) was observed in B-CK-/- mice. It is suggested that the persistent expression of the mitochondrial isoform ubiquitous mitochondrial CK (UbCKmit) in the creatine/phospho-creatine shuttle provides compensation for the loss of B-CK in the brain. Our studies indicate a role for the creatine-phosphocreatine/CK circuit in the formation or maintenance of hippocampal mossy fibre connections, and processes that involve habituation, spatial learning and seizure susceptibility. However, for fuelling of basic physiological activities the role of B-CK can be compensated for by other systems in the versatile and robust metabolic-energy network of the brain.
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http://dx.doi.org/10.1046/j.1460-9568.2002.02001.xDOI Listing
May 2002