Publications by authors named "Tanja Vogel"

30 Publications

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DOT1L-mediated murine neuronal differentiation associates with H3K79me2 accumulation and preserves SOX2-enhancer accessibility.

Nat Commun 2020 10 15;11(1):5200. Epub 2020 Oct 15.

Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.

During neuronal differentiation, the transcriptional profile and the epigenetic context of neural committed cells is subject to significant rearrangements, but a systematic quantification of global histone modification changes is still missing. Here, we show that H3K79me2 increases and H3K27ac decreases globally during in-vitro neuronal differentiation of murine embryonic stem cells. DOT1L mediates all three degrees of methylation of H3K79 and its enzymatic activity is critical to modulate cellular differentiation and reprogramming. In this context, we find that inhibition of DOT1L in neural progenitor cells biases the transcriptional state towards neuronal differentiation, resulting in transcriptional upregulation of genes marked with H3K27me3 on the promoter region. We further show that DOT1L inhibition affects accessibility of SOX2-bound enhancers and impairs SOX2 binding in neural progenitors. Our work provides evidence that DOT1L activity gates differentiation of progenitors by allowing SOX2-dependent transcription of stemness programs.
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http://dx.doi.org/10.1038/s41467-020-19001-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7562744PMC
October 2020

Differentiation and localization of interneurons in the developing spinal cord depends on DOT1L expression.

Mol Brain 2020 05 29;13(1):85. Epub 2020 May 29.

Department of Molecular Embryology, Institute of Anatomy and Cell Biology, Faculty of Medicine, Albert-Ludwigs-University Freiburg, 79104, Freiburg, Germany.

Genetic and epigenetic factors contribute to the development of the spinal cord. Failure in correct exertion of the developmental programs, including neurulation, neural tube closure and neurogenesis of the diverse spinal cord neuronal subtypes results in defects of variable severity. We here report on the histone methyltransferase Disruptor of Telomeric 1 Like (DOT1L), which mediates histone H3 lysine 79 (H3K79) methylation. Conditional inactivation of DOT1L using Wnt1-cre as driver (Dot1l-cKO) showed that DOT1L expression is essential for spinal cord neurogenesis and localization of diverse neuronal subtypes, similar to its function in the development of the cerebral cortex and cerebellum. Transcriptome analysis revealed that DOT1L deficiency favored differentiation over progenitor proliferation. Dot1l-cKO mainly decreased the numbers of dI1 interneurons expressing Lhx2. In contrast, Lhx9 expressing dI1 interneurons did not change in numbers but localized differently upon Dot1l-cKO. Similarly, loss of DOT1L affected localization but not generation of dI2, dI3, dI5, V0 and V1 interneurons. The resulting derailed interneuron patterns might be responsible for increased cell death, occurrence of which was restricted to the late developmental stage E18.5. Together our data indicate that DOT1L is essential for subtype-specific neurogenesis, migration and localization of dorsal and ventral interneurons in the developing spinal cord, in part by regulating transcriptional activation of Lhx2.
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http://dx.doi.org/10.1186/s13041-020-00623-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260853PMC
May 2020

Transcription and Beyond: Delineating FOXG1 Function in Cortical Development and Disorders.

Front Cell Neurosci 2020 25;14:35. Epub 2020 Feb 25.

Laboratory for Developmental Biology, Department of Biology, Faculty of Education and Integrated Arts and Sciences, Waseda University, Tokyo, Japan.

Forkhead Box G1 () is a member of the Forkhead family of genes with non-redundant roles in brain development, where alteration of this gene's expression significantly affects the formation and function of the mammalian cerebral cortex. haploinsufficiency in humans is associated with prominent differences in brain size and impaired intellectual development noticeable in early childhood, while homozygous mutations are typically fatal. As such, has been implicated in a wide spectrum of congenital brain disorders, including the congenital variant of Rett syndrome, infantile spasms, microcephaly, autism spectrum disorder (ASD) and schizophrenia. Recent technological advances have yielded greater insight into phenotypic variations observed in FOXG1 syndrome, molecular mechanisms underlying pathogenesis of the disease, and multifaceted roles of expression. In this review, we explore the emerging mechanisms of in a range of transcriptional to posttranscriptional events in order to evolve our current view of how a single transcription factor governs the assembly of an elaborate cortical circuit responsible for higher cognitive functions and neurological disorders.
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http://dx.doi.org/10.3389/fncel.2020.00035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052011PMC
February 2020

TGFβ-Signaling and FOXG1-Expression Are a Hallmark of Astrocyte Lineage Diversity in the Murine Ventral and Dorsal Forebrain.

Front Cell Neurosci 2018 28;12:448. Epub 2018 Nov 28.

Department of Molecular Embryology, Institute of Anatomy and Cell Biology, Medical Faculty, University of Freiburg, Freiburg, Germany.

Heterogeneous astrocyte populations are defined by diversity in cellular environment, progenitor identity or function. Yet, little is known about the extent of the heterogeneity and how this diversity is acquired during development. To investigate the impact of TGF (transforming growth factor) β-signaling on astrocyte development in the telencephalon we deleted the TGFBR2 (transforming growth factor beta receptor 2) in early neural progenitor cells in mice using a FOXG1 (forkhead box G1)-driven CRE-recombinase. We used quantitative proteomics to characterize TGFBR2-deficient cells derived from the mouse telencephalon and identified differential protein expression of the astrocyte proteins GFAP (glial fibrillary acidic protein) and MFGE8 (milk fat globule-EGF factor 8). Biochemical and histological investigations revealed distinct populations of astrocytes in the dorsal and ventral telencephalon marked by GFAP or MFGE8 protein expression. The two subtypes differed in their response to TGFβ-signaling. Impaired TGFβ-signaling affected numbers of GFAP astrocytes in the ventral telencephalon. In contrast, TGFβ reduced MFGE8-expression in astrocytes deriving from both regions. Additionally, lineage tracing revealed that both GFAP and MFGE8 astrocyte subtypes derived partly from FOXG1-expressing neural precursor cells.
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http://dx.doi.org/10.3389/fncel.2018.00448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282056PMC
November 2018

FOXG1 Regulates PRKAR2B Transcriptionally and Posttranscriptionally via miR200 in the Adult Hippocampus.

Mol Neurobiol 2019 Jul 11;56(7):5188-5201. Epub 2018 Dec 11.

Institute of Anatomy and Cell Biology, Department of Molecular Embryology, Faculty of Medicine, Albert-Ludwigs-University Freiburg, 79104, Freiburg, Germany.

Rett syndrome is a complex neurodevelopmental disorder that is mainly caused by mutations in MECP2. However, mutations in FOXG1 cause a less frequent form of atypical Rett syndrome, called FOXG1 syndrome. FOXG1 is a key transcription factor crucial for forebrain development, where it maintains the balance between progenitor proliferation and neuronal differentiation. Using genome-wide small RNA sequencing and quantitative proteomics, we identified that FOXG1 affects the biogenesis of miR200b/a/429 and interacts with the ATP-dependent RNA helicase, DDX5/p68. Both FOXG1 and DDX5 associate with the microprocessor complex, whereby DDX5 recruits FOXG1 to DROSHA. RNA-Seq analyses of Foxg1 hippocampi and N2a cells overexpressing miR200 family members identified cAMP-dependent protein kinase type II-beta regulatory subunit (PRKAR2B) as a target of miR200 in neural cells. PRKAR2B inhibits postsynaptic functions by attenuating protein kinase A (PKA) activity; thus, increased PRKAR2B levels may contribute to neuronal dysfunctions in FOXG1 syndrome. Our data suggest that FOXG1 regulates PRKAR2B expression both on transcriptional and posttranscriptional levels.
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http://dx.doi.org/10.1007/s12035-018-1444-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6647430PMC
July 2019

DOT1L promotes progenitor proliferation and primes neuronal layer identity in the developing cerebral cortex.

Nucleic Acids Res 2019 01;47(1):168-183

Institute of Anatomy and Cell Biology, Department of Molecular Embryology, Medical Faculty, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany.

Cortical development is controlled by transcriptional programs, which are orchestrated by transcription factors. Yet, stable inheritance of spatio-temporal activity of factors influencing cell fate and localization in different layers is only partly understood. Here we find that deletion of Dot1l in the murine telencephalon leads to cortical layering defects, indicating DOT1L activity and chromatin methylation at H3K79 impact on the cell cycle, and influence transcriptional programs conferring upper layer identity in early progenitors. Specifically, DOT1L prevents premature differentiation by increasing expression of genes that regulate asymmetric cell division (Vangl2, Cenpj). Loss of DOT1L results in reduced numbers of progenitors expressing genes including SoxB1 gene family members. Loss of DOT1L also leads to altered cortical distribution of deep layer neurons that express either TBR1, CTIP2 or SOX5, and less activation of transcriptional programs that are characteristic for upper layer neurons (Satb2, Pou3f3, Cux2, SoxC family members). Data from three different mouse models suggest that DOT1L balances transcriptional programs necessary for proper neuronal composition and distribution in the six cortical layers. Furthermore, because loss of DOT1L in the pre-neurogenic phase of development impairs specifically generation of SATB2-expressing upper layer neurons, our data suggest that DOT1L primes upper layer identity in cortical progenitors.
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http://dx.doi.org/10.1093/nar/gky953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326801PMC
January 2019

Differential Methylation of H3K79 Reveals DOT1L Target Genes and Function in the Cerebellum In Vivo.

Mol Neurobiol 2019 Jun 10;56(6):4273-4287. Epub 2018 Oct 10.

Institute for Anatomy and Cell Biology, Department of Molecular Embryology, Medical Faculty, University of Freiburg, 79104, Freiburg, Germany.

The disruptor of telomeric silencing 1-like (DOT1L) mediates methylation of histone H3 at position lysine 79 (H3K79). Conditional knockout of Dot1l in mouse cerebellar granule cells (Dot1l-cKO) led to a smaller external granular layer with fewer precursors of granule neurons. Dot1l-cKO mice had impaired proliferation and differentiation of granular progenitors, which resulted in a smaller cerebellum. Mutant mice showed mild ataxia in motor behavior tests. In contrast, Purkinje cell-specific conditional knockout mice showed no obvious phenotype. Genome-wide transcription analysis of Dot1l-cKO cerebella using microarrays revealed changes in genes that function in cell cycle, cell migration, axon guidance, and metabolism. To identify direct DOT1L target genes, we used genome-wide profiling of H3K79me2 and transcriptional analysis. Analysis of differentially methylated regions (DR) and differentially expressed genes (DE) revealed in total 12 putative DOT1L target genes in Dot1l-cKO affecting signaling (Tnfaip8l3, B3galt5), transcription (Otx1), cell migration and axon guidance (Sema4a, Sema5a, Robo1), cholesterol and lipid metabolism (Lss, Cyp51), cell cycle (Cdkn1a), calcium-dependent cell-adhesion or exocytosis (Pcdh17, Cadps2), and unknown function (Fam174b). Dysregulated expression of these target genes might be implicated in the ataxia phenotype observed in Dot1l-cKO.
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http://dx.doi.org/10.1007/s12035-018-1377-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505521PMC
June 2019

DGCR8 Promotes Neural Progenitor Expansion and Represses Neurogenesis in the Mouse Embryonic Neocortex.

Front Neurosci 2018 30;12:281. Epub 2018 Apr 30.

Neurobiology of miRNA Laboratory, Department of Neuroscience and Brain Technologies, Fondazione Istituto Italiano di Tecnologia, Genoa, Italy.

DGCR8 and DROSHA are the minimal functional core of the Microprocessor complex essential for biogenesis of canonical microRNAs and for the processing of other RNAs. Conditional deletion of and in the murine telencephalon indicated that these proteins exert crucial functions in corticogenesis. The identification of mechanisms of DGCR8- or DROSHA-dependent regulation of gene expression in conditional knockout mice are often complicated by massive apoptosis. Here, to investigate DGCR8 functions on amplification/differentiation of neural progenitors cells (NPCs) in corticogenesis, we overexpress in the mouse telencephalon, by electroporation (Ep). We find that DGCR8 promotes the expansion of NPC pools and represses neurogenesis, in absence of apoptosis, thus overcoming the usual limitations of knockout-based approach. Interestingly, DGCR8 selectively promotes basal progenitor amplification at later developmental stages, entailing intriguing implications for neocortical expansion in evolution. Finally, despite a 3- to 5-fold increase of DGCR8 level in the mouse telencephalon, the composition, target preference and function of the DROSHA-dependent Microprocessor complex remain unaltered. Thus, we propose that DGCR8-dependent modulation of gene expression in corticogenesis is more complex than previously known, and possibly DROSHA-independent.
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http://dx.doi.org/10.3389/fnins.2018.00281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5936999PMC
April 2018

Isolation and Cultivation of Neural Progenitors Followed by Chromatin-Immunoprecipitation of Histone 3 Lysine 79 Dimethylation Mark.

J Vis Exp 2018 01 26(131). Epub 2018 Jan 26.

Institute for Anatomy and Cell Biology, Department of Molecular Embryology, Faculty of Medicine, University of Freiburg;

Brain development is a complex process, which is controlled in a temporo-spatial manner by gradients of morphogens and different transcriptional programs. Additionally, epigenetic chromatin modifications, like histone methylation, have an important role for establishing and maintaining specific cell fates within this process. The vast majority of histone methylation occurs on the flexible histone tail, which is accessible to histone modifiers, erasers, and histone reader proteins. In contrast, H3K79 methylation is located in the globular domain of histone 3 and is implicated in different developmental functions. H3K79 methylation is evolutionarily conserved and can be found in a wide range of species from Homo sapiens to Saccharomyces cerevisiae. The modification occurs in different cell populations within organisms, including neural progenitors. The location of H3K79 methylation in the globular domain of histone 3 makes it difficult to assess. Here, we present methods to isolate and culture cortical progenitor cells (CPCs) from embryonic cortical brain tissue (E11.5-E14.5) or cerebellar granular neuron progenitors (CGNPs) from postnatal tissue (P5-P7), and to efficiently immunoprecipitate H3K79me2 for quantitative PCR (qPCR) and genome-wide sequencing.
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http://dx.doi.org/10.3791/56631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5908698PMC
January 2018

Neuronal Activity, TGFβ-Signaling and Unpredictable Chronic Stress Modulate Transcription of Gadd45 Family Members and DNA Methylation in the Hippocampus.

Cereb Cortex 2017 08;27(8):4166-4181

Department of Molecular Embryology, Institute of Anatomy and Cell Biology, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany.

Neuronal activity is altered in several neurological and psychiatric diseases. Upon depolarization not only neurotransmitters are released but also cytokines and other activators of signaling cascades. Unraveling their complex implication in transcriptional control in receiving cells will contribute to understand specific central nervous system (CNS) pathologies and will be of therapeutically interest. In this study we depolarized mature hippocampal neurons in vitro using KCl and revealed increased release not only of brain-derived neurotrophic factor (BDNF) but also of transforming growth factor beta (TGFB). Neuronal activity together with BDNF and TGFB controls transcription of DNA modifying enzymes specifically members of the DNA-damage-inducible (Gadd) family, Gadd45a, Gadd45b, and Gadd45g. MeDIP followed by massive parallel sequencing and transcriptome analyses revealed less DNA methylation upon KCl treatment. Psychiatric disorder-related genes, namely Tshz1, Foxn3, Jarid2, Per1, Map3k5, and Arc are transcriptionally activated and demethylated upon neuronal activation. To analyze whether misexpression of Gadd45 family members are associated with psychiatric diseases, we applied unpredictable chronic mild stress (UCMS) as established model for depression to mice. UCMS led to reduced expression of Gadd45 family members. Taken together, our data demonstrate that Gadd45 family members are new putative targets for UCMS treatments.
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http://dx.doi.org/10.1093/cercor/bhx095DOI Listing
August 2017

A SLM2 Feedback Pathway Controls Cortical Network Activity and Mouse Behavior.

Cell Rep 2016 12;17(12):3269-3280

Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK. Electronic address:

The brain is made up of trillions of synaptic connections that together form neural networks needed for normal brain function and behavior. SLM2 is a member of a conserved family of RNA binding proteins, including Sam68 and SLM1, that control splicing of Neurexin1-3 pre-mRNAs. Whether SLM2 affects neural network activity is unknown. Here, we find that SLM2 levels are maintained by a homeostatic feedback control pathway that predates the divergence of SLM2 and Sam68. SLM2 also controls the splicing of Tomosyn2, LysoPLD/ATX, Dgkb, Kif21a, and Cask, each of which are important for synapse function. Cortical neural network activity dependent on synaptic connections between SLM2-expressing-pyramidal neurons and interneurons is decreased in Slm2-null mice. Additionally, these mice are anxious and have a decreased ability to recognize novel objects. Our data reveal a pathway of SLM2 homeostatic auto-regulation controlling brain network activity and behavior.
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http://dx.doi.org/10.1016/j.celrep.2016.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5199341PMC
December 2016

The FOXG1/FOXO/SMAD network balances proliferation and differentiation of cortical progenitors and activates Kcnh3 expression in mature neurons.

Oncotarget 2016 Jun;7(25):37436-37455

Department of Molecular Embryology, Institute of Anatomy and Cell Biology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Transforming growth factor β (TGFβ)-mediated anti-proliferative and differentiating effects promote neuronal differentiation during embryonic central nervous system development. TGFβ downstream signals, composed of activated SMAD2/3, SMAD4 and a FOXO family member, promote the expression of cyclin-dependent kinase inhibitor Cdkn1a. In early CNS development, IGF1/PI3K signaling and the transcription factor FOXG1 inhibit FOXO- and TGFβ-mediated Cdkn1a transcription. FOXG1 prevents cell cycle exit by binding to the SMAD/FOXO-protein complex. In this study we provide further details on the FOXG1/FOXO/SMAD transcription factor network. We identified ligands of the TGFβ- and IGF-family, Foxo1, Foxo3 and Kcnh3 as novel FOXG1-target genes during telencephalic development and showed that FOXG1 interferes with Foxo1 and Tgfβ transcription. Our data specify that FOXO1 activates Cdkn1a transcription. This process is under control of the IGF1-pathway, as Cdkn1a transcription increases when IGF1-signaling is pharmacologically inhibited. However, overexpression of CDKN1A and knockdown of Foxo1 and Foxo3 is not sufficient for neuronal differentiation, which is probably instructed by TGFβ-signaling. In mature neurons, FOXG1 activates transcription of the seizure-related Kcnh3, which might be a FOXG1-target gene involved in the FOXG1 syndrome pathology.
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http://dx.doi.org/10.18632/oncotarget.9545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5122323PMC
June 2016

Axonopathy in the Central Nervous System Is the Hallmark of Mice with a Novel Intragenic Null Mutation of Dystonin.

Genetics 2016 Sep 8;204(1):191-203. Epub 2016 Jul 8.

Animal Facility, Max Planck Institute for Biophysical Chemistry, D-37077 Göttingen, Germany

Dystonia musculorum is a neurodegenerative disorder caused by a mutation in the dystonin gene. It has been described in mice and humans where it is called hereditary sensory autonomic neuropathy. Mutated mice show severe movement disorders and die at the age of 3-4 weeks. This study describes the discovery and molecular, clinical, as well as pathological characterization of a new spontaneously occurring mutation in the dystonin gene in C57BL/6N mice. The mutation represents a 40-kb intragenic deletion allele of the dystonin gene on chromosome 1 with exactly defined deletion borders. It was demonstrated by Western blot, mass spectrometry, and immunohistology that mice with a homozygous mutation were entirely devoid of the dystonin protein. Pathomorphological lesions were restricted to the brain stem and spinal cord and consisted of swollen, argyrophilic axons and dilated myelin sheaths in the white matter and, less frequently, total chromatolysis of neurons in the gray matter. Axonal damage was detected by amyloid precursor protein and nonphosphorylated neurofilament immunohistology. Axonopathy in the central nervous system (CNS) represents the hallmark of this disease. Mice with the dystonin mutation also showed suppurative inflammation in the respiratory tract, presumably due to brain stem lesion-associated food aspiration, whereas skeletal muscles showed no pathomorphological changes. This study describes a novel mutation in the dystonin gene in mice leading to axonopathy in the CNS. In further studies, this model may provide new insights into the pathogenesis of neurodegenerative diseases and may elucidate the complex interactions of dystonin with various other cellular proteins especially in the CNS.
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http://dx.doi.org/10.1534/genetics.116.186932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5012385PMC
September 2016

Is attention deficit/hyperactivity disorder among men associated with initiation or escalation of substance use at 15-month follow-up? A longitudinal study involving young Swiss men.

Addiction 2016 10 26;111(10):1867-78. Epub 2016 May 26.

University Hospital of Psychiatry, University of Bern, Bern, Switzerland.

Background And Aims: Young adults with attention deficit/hyperactivity disorder (ADHD) show higher substance use disorder (SUD) prevalence relative to non-ADHD controls; few longitudinal studies have examined the course of substance use with reference to conduct disorder (CD). We compared initiation and escalation of substance use at 15-month follow-up in men screened positive or negative for ADHD (ADHD(+) versus ADHD(-) ), controlling for CD presence in early adolescence.

Design: Participants were recruited during August 2010 and November 2011 from the census of all young men who have to pass mandatory army conscription from three of six Swiss Army recruitment centres. A two-wave data collection was performed via questionnaires at baseline and 15-month follow-up as a part of the longitudinal Cohort Study on Substance Use Risk Factors.

Setting: Recruitment centres in Lausanne, Windisch and Mels, responsible for 21 cantons in German- and French-speaking areas of Switzerland.

Participants: Consecutive sample of 5103 male Swiss Army conscripts who provided informed consent and responded to questionnaires at baseline and 15-month follow-up. Their mean age was 20.0 (standard deviation = 1.21) years at baseline.

Measurements: ADHD and CD were assessed using the adult ADHD Self-Report Scale and the MINI International Neuropsychiatric Interview Plus, respectively, at baseline, and substance use was measured via self-administered substance use questionnaires at baseline and follow-up.

Findings: Compared with the ADHD(-) group, the ADHD(+) group (n = 215, 4.2%) showed heavier baseline substance use and increased likelihood of alcohol (χ(2)  = 53.96; P < 0.001), tobacco (χ(2)  = 21.73; P < 0.001) and cannabis use disorders (χ(2)  = 48.43; P < 0.001). The extent of alcohol, tobacco and cannabis use in the two groups remained stable from baseline to follow-up (no escalation). The ADHD(+) group was more likely to initiate substance use compared with the ADHD(-) group (higher initiation rates), particularly with amphetamines [odds ratio (OR) = 3.81; 95% confidence interval (CI) = 2.20-6.60; P < 0.001] and non-medical use of ADHD medication (OR = 4.45; 95% CI = 2.06-9.60; P < 0.001). CD was associated with initiation of substance use but did not mediate the associations between ADHD and substance use, revealing that the impact of ADHD on substance use was independent of CD.

Conclusions: For men in their early 20s, attention deficit/hyperactivity disorder is a risk factor for continued heavier but not escalating use of alcohol, tobacco and cannabis when already consuming these substances, compared with young men with no ADHD. It is also a risk factor for initiating the use of cannabis, stimulants, hallucinogens and sedatives, independent of conduct disorder in early adolescence.
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http://dx.doi.org/10.1111/add.13422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215781PMC
October 2016

Usp22 deficiency impairs intestinal epithelial lineage specification in vivo.

Oncotarget 2015 Nov;6(35):37906-18

Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075 Göttingen, Germany.

Epigenetic regulatory mechanisms play a central role in controlling gene expression during development, cell differentiation and tumorigenesis. Monoubiquitination of histone H2B is one epigenetic modification which is dynamically regulated by the opposing activities of specific ubiquitin ligases and deubiquitinating enzymes (DUBs). The Ubiquitin-specific Protease 22 (USP22) is the ubiquitin hydrolase component of the human SAGA complex which deubiquitinates histone H2B during transcription. Recently, many studies have investigated an oncogenic potential of USP22 overexpression. However, its physiological function in organ maintenance, development and its cellular function remain largely unknown. A previous study reported embryonic lethality in Usp22 knockout mice. Here we describe a mouse model with a global reduction of USP22 levels which expresses the LacZ gene under the control of the endogenous Usp22 promoter. Using this reporter we found Usp22 to be ubiquitously expressed in murine embryos. Notably, adult Usp2(2lacZ/lacZ) displayed low residual Usp22 expression levels coupled with a reduced body size and weight. Interestingly, the reduction of Usp22 significantly influenced the frequency of differentiated cells in the small intestine and the brain while H2B and H2Bub1 levels remained constant. Taken together, we provide evidence for a physiological role for USP22 in controlling cell differentiation and lineage specification.
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http://dx.doi.org/10.18632/oncotarget.5412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741973PMC
November 2015

DOT1L Activity Promotes Proliferation and Protects Cortical Neural Stem Cells from Activation of ATF4-DDIT3-Mediated ER Stress In Vitro.

Stem Cells 2016 Jan 29;34(1):233-45. Epub 2015 Sep 29.

Department of Molecular Embryology, Institute of Anatomy and Cell Biology, Albert-Ludwigs-University, Freiburg, Freiburg, Germany.

Growing evidence suggests that the lysine methyltransferase DOT1L/KMT4 has important roles in proliferation, survival, and differentiation of stem cells in development and in disease. We investigated the function of DOT1L in neural stem cells (NSCs) of the cerebral cortex. The pharmacological inhibition and shRNA-mediated knockdown of DOT1L impaired proliferation and survival of NSCs. DOT1L inhibition specifically induced genes that are activated during the unfolded protein response (UPR) in the endoplasmic reticulum (ER). Chromatin-immunoprecipitation analyses revealed that two genes encoding for central molecules involved in the ER stress response, Atf4 and Ddit3 (Chop), are marked with H3K79 methylation. Interference with DOT1L activity resulted in transcriptional activation of both genes accompanied by decreased levels of H3K79 dimethylation. Although downstream effectors of the UPR, such as Ppp1r15a/Gadd34, Atf3, and Tnfrsf10b/Dr5 were also transcriptionally activated, this most likely occurred in response to increased ATF4 expression rather than as a direct consequence of altered H3K79 methylation. While stem cells are particularly vulnerable to stress, the UPR and ER stress have not been extensively studied in these cells yet. Since activation of the ER stress program is also implicated in directing stem cells into differentiation or to maintain a proliferative status, the UPR must be tightly regulated. Our and published data suggest that histone modifications, including H3K4me3, H3K14ac, and H3K79me2, are implicated in the control of transcriptional activation of ER stress genes. In this context, the loss of H3K79me2 at the Atf4- and Ddit3-promoters appears to mark a point-of-no-return that activates the death program in NSCs.
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http://dx.doi.org/10.1002/stem.2187DOI Listing
January 2016

Neural deletion of Tgfbr2 impairs angiogenesis through an altered secretome.

Hum Mol Genet 2014 Dec 2;23(23):6177-90. Epub 2014 Jul 2.

Department of Molecular Embryology, Institute of Anatomy and Cell Biology, University of Freiburg, 79104 Freiburg, Germany,

Simultaneous generation of neural cells and that of the nutrient-supplying vasculature during brain development is called neurovascular coupling. We report on a transgenic mouse with impaired transforming growth factor β (TGFβ)-signalling in forebrain-derived neural cells using a Foxg1-cre knock-in to drive the conditional knock-out of the Tgfbr2. Although the expression of FOXG1 is assigned to neural progenitors and neurons of the telencephalon, Foxg1(cre/+);Tgfbr2(flox/flox) (Tgfbr2-cKO) mutants displayed intracerebral haemorrhage. Blood vessels exhibited an atypical, clustered appearance were less in number and displayed reduced branching. Vascular endothelial growth factor (VEGF) A, insulin-like growth factor (IGF) 1, IGF2, TGFβ, inhibitor of DNA binding (ID) 1, thrombospondin (THBS) 2, and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) 1 were altered in either expression levels or tissue distribution. Accordingly, human umbilical vein endothelial cells (HUVEC) displayed branching defects after stimulation with conditioned medium (CM) that was derived from primary neural cultures of the ventral and dorsal telencephalon of Tgfbr2-cKO. Supplementing CM of Tgfbr2-cKO with VEGFA rescued these defects, but application of TGFβ aggravated them. HUVEC showed reduced migration towards CM of mutants compared with controls. Supplementing the CM with growth factors VEGFA, fibroblast growth factor (FGF) 2 and IGF1 partially restored HUVEC migration. In contrast, TGFβ supplementation further impaired migration of HUVEC. We observed differences along the dorso-ventral axis of the telencephalon with regard to the impact of these factors on the phenotype. Together these data establish a TGFBR2-dependent molecular crosstalk between neural and endothelial cells during brain vessel development. These findings will be useful to further elucidate neurovascular interaction in general and to understand pathologies of the blood vessel system such as intracerebral haemorrhages, hereditary haemorrhagic telangiectasia, Alzheimeŕs disease, cerebral amyloid angiopathy or tumour biology.
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http://dx.doi.org/10.1093/hmg/ddu338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4222361PMC
December 2014

Epigenetics: development, dynamics and disease.

Cell Tissue Res 2014 Jun;356(3):451-5

Department of Molecular Embryology, Institute for Anatomy and Cell Biology, Albertstrasse 17, Freiburg, 79104, Germany,

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http://dx.doi.org/10.1007/s00441-014-1916-7DOI Listing
June 2014

Biological and bioinformatical approaches to study crosstalk of long-non-coding RNAs and chromatin-modifying proteins.

Cell Tissue Res 2014 Jun 13;356(3):507-26. Epub 2014 May 13.

Institute of Computer Science, Albert-Ludwigs-University, Freiburg, Germany.

Long-non-coding RNA (lncRNA) regulates gene expression through transcriptional and epigenetic regulation as well as alternative splicing in the nucleus. In addition, regulation is achieved at the levels of mRNA translation, storage and degradation in the cytoplasm. During recent years, several studies have described the interaction of lncRNAs with enzymes that confer so-called epigenetic modifications, such as DNA methylation, histone modifications and chromatin structure or remodelling. LncRNA interaction with chromatin-modifying enzymes (CME) is an emerging field that confers another layer of complexity in transcriptional regulation. Given that CME-lncRNA interactions have been identified in many biological processes, ranging from development to disease, comprehensive understanding of underlying mechanisms is important to inspire basic and translational research in the future. In this review, we highlight recent findings to extend our understanding about the functional interdependencies between lncRNAs and CMEs that activate or repress gene expression. We focus on recent highlights of molecular and functional roles for CME-lncRNAs and provide an interdisciplinary overview of recent technical and methodological developments that have improved biological and bioinformatical approaches for detection and functional studies of CME-lncRNA interaction.
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http://dx.doi.org/10.1007/s00441-014-1885-xDOI Listing
June 2014

PI3K-p110-alpha-subtype signalling mediates survival, proliferation and neurogenesis of cortical progenitor cells via activation of mTORC2.

J Neurochem 2014 Jul 3;130(2):255-67. Epub 2014 May 3.

Department of Molecular Embryology, Institute of Anatomy and Cell Biology, Albert-Ludwigs-University Freiburg, Freiburg, Germany; Faculty of Biology, Albert-Ludwigs-University Freiburg, Freiburg, Germany.

Development of the cerebral cortex is controlled by growth factors among which transforming growth factor beta (TGFβ) and insulin-like growth factor 1 (IGF1) have a central role. The TGFβ- and IGF1-pathways cross-talk and share signalling molecules, but in the central nervous system putative points of intersection remain unknown. We studied the biological effects and down-stream molecules of TGFβ and IGF1 in cells derived from the mouse cerebral cortex at two developmental time points, E13.5 and E16.5. IGF1 induces PI3K, AKT and the mammalian target of rapamycin complexes (mTORC1/mTORC2) primarily in E13.5-derived cells, resulting in proliferation, survival and neuronal differentiation, but has small impact on E16.5-derived cells. TGFβ has little effect at E13.5. It does not activate the PI3K- and mTOR-signalling network directly, but requires its activity to mediate neuronal differentiation specifically at E16.5. Our data indicate a central role of mTORC2 in survival, proliferation as well as neuronal differentiation of E16.5-derived cortical cells. mTORC2 promotes these cellular processes and is under control of PI3K-p110-alpha signalling. PI3K-p110-beta signalling activates mTORC2 in E16.5-derived cells but it does not influence cell survival, proliferation and differentiation. This finding indicates that different mTORC2 subtypes may be implicated in cortical development and that these subtypes are under control of different PI3K isoforms. Within developing cortical cells TGFβ- and IGF-signalling activities are timely separated. TGFβ dominates in E16.5-derived cells and drives neuronal differentiation. IGF influences survival, proliferation and neuronal differentiation in E13.5-derived cells. mTORC2-signalling in E16.5-derived cells influences survival, proliferation and differentiation, activated through PI3K-p110-alpha. PI3K-p110-beta-signalling activates a different mTORC2. Both PI3K/mTORC2-signalling pathways are required but not directly activated in TGFβ-mediated neuronal differentiation.
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http://dx.doi.org/10.1111/jnc.12718DOI Listing
July 2014

The histone H2B monoubiquitination regulatory pathway is required for differentiation of multipotent stem cells.

Mol Cell 2012 Jun;46(5):705-13

Department of Molecular Oncology, Göttingen Center for Molecular Biosciences, University Medical Center Göttingen, Göttingen 37077, Germany.

Extensive changes in posttranslational histone modifications accompany the rewiring of the transcriptional program during stem cell differentiation. However, the mechanisms controlling the changes in specific chromatin modifications and their function during differentiation remain only poorly understood. We show that histone H2B monoubiquitination (H2Bub1) significantly increases during differentiation of human mesenchymal stem cells (hMSCs) and various lineage-committed precursor cells and in diverse organisms. Furthermore, the H2B ubiquitin ligase RNF40 is required for the induction of differentiation markers and transcriptional reprogramming of hMSCs. This function is dependent upon CDK9 and the WAC adaptor protein, which are required for H2B monoubiquitination. Finally, we show that RNF40 is required for the resolution of the H3K4me3/H3K27me3 bivalent poised state on lineage-specific genes during the transition from an inactive to an active chromatin conformation. Thus, these data indicate that H2Bub1 is required for maintaining multipotency of hMSCs and plays a central role in controlling stem cell differentiation.
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http://dx.doi.org/10.1016/j.molcel.2012.05.022DOI Listing
June 2012

In vivo measurement of the human epidermal thickness in different localizations by multiphoton laser tomography.

Skin Res Technol 2010 Aug;16(3):259-64

Department of Dermatology and Allergology, Friedrich Schiller University, Jena, Germany.

Background: The in vivo measurement of epidermal thickness is still challenging. While ultrasound, optical coherence tomography and confocal laser microscopy are used with moderate success, this issue has not been addressed by multiphoton laser tomography.

Objectives: In the present study, an in vivo measurement of four different morphometric epidermal parameters is performed.

Methods: Thirty healthy volunteers aged 21-82 years were included in the study after informed consent and approval of the local ethics committee. At the dorsal forearm and the dorsum of the hand, the thicknesses of the total epidermis, viable epidermis and stratum corneum and the depth of the papillary dermis were calculated from depth-resolved intensity curves after correlation with multiphoton images.

Results: We have shown consistently that in all age groups, the four morphometric parameters are significantly higher at the hand compared with the forearm, while there were no differences between age groups. This is consistent with most previous findings.

Conclusion: The method presented here provides a novel in vivo investigation tool for the measurement of epidermal morphometric parameters that may be useful for the observation of epidermal changes over time in skin disorders, therapy side effects or in cosmetic science.
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http://dx.doi.org/10.1111/j.1600-0846.2010.00437.xDOI Listing
August 2010

Af9/Mllt3 interferes with Tbr1 expression through epigenetic modification of histone H3K79 during development of the cerebral cortex.

Proc Natl Acad Sci U S A 2010 Apr 26;107(15):7042-7. Epub 2010 Mar 26.

Centre of Anatomy, Department of Neuroanatomy, University Medical Centre Goettingen, Georg-August-University, 37075 Goettingen, Germany.

Mutations of leukemia-associated AF9/MLLT3 are implicated in neurodevelopmental diseases, such as epilepsy and ataxia, but little is known about how AF9 influences brain development and function. Analyses of mouse mutants revealed that during cortical development, AF9 is involved in the maintenance of TBR2-positive progenitors (intermediate precursor cells, IPCs) in the subventricular zone and prevents premature cell cycle exit of IPCs. Furthermore, in postmitotic neurons of the developing cortical plate, AF9 is implicated in the formation of the six-layered cerebral cortex by suppressing a TBR1-positive cell fate mainly in upper layer neurons. We show that the molecular mechanism of TBR1 suppression is based on the interaction of AF9 with DOT1L, a protein that mediates transcriptional control through methylation of histone H3 lysine 79 (H3K79). AF9 associates with the transcriptional start site of Tbr1, mediates H3K79 dimethylation of the Tbr1 gene, and interferes with the presence of RNA polymerase II at the Tbr1 transcriptional start site. AF9 expression favors cytoplasmic localization of TBR1 and its association with mitochondria. Increased expression of TBR1 in Af9 mutants is associated with increased levels of TBR1-regulated expression of NMDAR subunit Nr1. Thus, this study identified AF9 as a developmental active epigenetic modifier during the generation of cortical projection neurons.
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http://dx.doi.org/10.1073/pnas.0912041107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2872432PMC
April 2010

Transforming growth factor beta promotes neuronal cell fate of mouse cortical and hippocampal progenitors in vitro and in vivo: identification of Nedd9 as an essential signaling component.

Cereb Cortex 2010 Mar 8;20(3):661-71. Epub 2009 Jul 8.

Department of Neuroanatomy, Centre of Anatomy, Georg-August-University, 37075 Goettingen, Germany.

Transforming Growth Factor beta (Tgfbeta) and associated signaling effectors are expressed in the forebrain, but little is known about the role of this multifunctional cytokine during forebrain development. Using hippocampal and cortical primary cell cultures of developing mouse brains, this study identified Tgfbeta-regulated genes not only associated with cell cycle exit of progenitors but also with adoption of neuronal cell fate. Accordingly, we observed not only an antimitotic effect of Tgfbeta on progenitors but also an increased expression of neuronal markers in Tgfbeta treated cultures. This effect was dependent upon Smad4. Furthermore, in vivo loss-of-function analyses using Tgfbeta2(-/-)/Tgfbeta3(-/-) double mutant mice showed the opposite effect of increased cell proliferation and fewer neurons in the cerebral cortex and hippocampus. Gata2, Runx1, and Nedd9 were candidate genes regulated by Tgfbeta and known to be involved in developmental processes of neuronal progenitors. Using siRNA-mediated knockdown, we identified Nedd9 as an essential signaling component for the Tgfbeta-dependent increase in neuronal cell fate. Expression of this scaffolding protein, which is mainly described as a signaling molecule of the beta1-integrin pathway, was not only induced after Tgfbeta treatment but was also associated with morphological changes of the Nestin-positive progenitor pool observed upon exposure to Tgfbeta.
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http://dx.doi.org/10.1093/cercor/bhp134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2820705PMC
March 2010

Involvement of Fractin in TGF-beta-induced apoptosis in oligodendroglial progenitor cells.

Glia 2009 Nov;57(15):1619-29

Center of Anatomy, Department of Neuroanatomy, Georg-August-University, Goettingen, Germany.

Transforming growth factor-beta (TGF-beta) induces apoptotic cell death during the development of the nervous system. We recently identified that TGF-beta induced apoptosis in oligodendroglial progenitor cells (primary cells as well as oligodendroglial cell line OLI-neu) is characterized by down-regulation of Bcl-xl. In this report, we now focused on mechanisms that mediate TGF-beta dependent Bcl-xl down-regulation in oligodendroglial cells. We showed that the caspase-specific cleavage product Fractin is produced in oligodendroglial cells during TGF-beta-mediated apoptosis, which represents an early event of the cascade. Cleavage of actin into Fractin was dependent on functional actin and caspases, and occurred simultaneously with a Fractin-Bcl-xl-interaction. This Fractin-Bcl-xl interaction indicated a connection between Bcl-xl down-regulation and Fractin appearance, since Bcl-xl regulation was also dependent on caspases and functional actin, and an overexpression of Fractin induced a Bcl-xl protein down-regulation. Further analysis of Fractin-Bcl-xl interaction in other culture systems confirmed these data. In conclusion, we show that Fractin is not only an apoptotic marker, but has indeed a functional role in apoptotic signaling in oligodendrocytes.
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http://dx.doi.org/10.1002/glia.20875DOI Listing
November 2009

TGF-beta superfamily members, ActivinA and TGF-beta1, induce apoptosis in oligodendrocytes by different pathways.

Cell Tissue Res 2008 Dec 11;334(3):327-38. Epub 2008 Nov 11.

Centre of Anatomy, Department of Neuroanatomy, Georg August University, Goettingen, Germany.

Activins and transforming growth factor (TGF)-betas, members of the TGF-beta superfamily, affect numerous physiological processes, including apoptosis, in a variety of organs and tissues. Apoptotic functions of TGF-betas, in contrast to those of the activins, are well documented in the developing and adult nervous system. TGF-betas operate in a context-dependent manner and cooperate with other cytokines in the regulation of apoptosis. In this study, we show, for the first time, an apoptotic function of ActivinA in the nervous system, i.e. in oligodendroglial progenitor cells. Using the oligodendroglial cell line OLI-neu, we show that ActivinA acts autonomously, without cooperating with TGF-beta. In contrast to the mechanism of TGF-beta-mediated apoptosis involving Bcl-xl down-regulation, Bcl-xl in ActivinA-induced apoptosis is classically sequestered by the BH3-only protein Puma. Puma expression is controlled by the transcription factor p53 as demonstrated by experiments with the p53 inhibitor Pifithrin-alpha. Furthermore, in the apoptotic TGF-beta pathway, caspase-3 is activated, whereas in the apoptotic ActivinA pathway, apoptosis-inducing factor is released to trigger DNA fragmentation. These data suggest that TGF-beta and ActivinA induce apoptosis in oligodendrocytes by different apoptotic pathways.
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http://dx.doi.org/10.1007/s00441-008-0714-5DOI Listing
December 2008

Expression of Leukaemia associated transcription factor Af9/Mllt3 in the cerebral cortex of the mouse.

Gene Expr Patterns 2009 Feb 25;9(2):83-93. Epub 2008 Oct 25.

Georg-August-University Goettingen, Centre of Anatomy, Department of Neuroanatomy, Kreuzbergring 36, 37075 Goettingen, Germany.

Mutations of leukaemia associated AF9/MLLT3 are implicated in neurodevelopmental diseases such as epilepsia and ataxia. This study shows for the first time, that murine Af9 is transcribed in various CNS structures including the subventricular zone (SVZ) of the cerebral cortex, hippocampus, cerebellar cortex, septum and various thalamic structures, the choroid plexus, and the midbrain/hindbrain boundary. Expression of Af9 in the SVZ overlaps with Svet1, Cux2, and partially with Tbr2, confining its activity to the neurogenic compartment of the SVZ. In contrast to Svet1 and Cux2 expression, Af9 transcription is not limited to upper layer neurons but is found in the entire cortical plate. As part of an extensive network of interacting proteins involved in epigenetic DNA modification, we could show overlapping expression of Af9 with Af4/Aff1 and Fmr2/Aff2, two genes that are also related to neurodevelopmental diseases, as well as with the highly homologous Enl.
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http://dx.doi.org/10.1016/j.gep.2008.10.004DOI Listing
February 2009

Satb2 is a postmitotic determinant for upper-layer neuron specification in the neocortex.

Neuron 2008 Feb;57(3):378-92

Max-Planck-Institute for Experimental Medicine, Hermann-Rein Strasse 3, 37075 Göttingen, Germany.

Pyramidal neurons of the neocortex can be subdivided into two major groups: deep- (DL) and upper-layer (UL) neurons. Here we report that the expression of the AT-rich DNA-binding protein Satb2 defines two subclasses of UL neurons: UL1 (Satb2 positive) and UL2 (Satb2 negative). In the absence of Satb2, UL1 neurons lose their identity and activate DL- and UL2-specific genetic programs. UL1 neurons in Satb2 mutants fail to migrate to superficial layers and do not contribute to the corpus callosum but to the corticospinal tract, which is normally populated by DL axons. Ctip2, a gene required for the formation of the corticospinal tract, is ectopically expressed in all UL1 neurons in the absence of Satb2. Satb2 protein interacts with the Ctip2 genomic region and controls chromatin remodeling at this locus. Satb2 therefore is required for the initiation of the UL1-specific genetic program and for the inactivation of DL- and UL2-specific genes.
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http://dx.doi.org/10.1016/j.neuron.2007.12.028DOI Listing
February 2008

Differential expression of polycomb repression complex 1 (PRC1) members in the developing mouse brain reveals multiple complexes.

Dev Dyn 2006 Sep;235(9):2574-85

Department of Molecular Cell Biology, Max-Planck-Institute for Biophysical Chemistry, Karl-Friedrich-Bonhoeffer-Institute, Goettingen, Germany.

Polycomb group (PcG) genes are regulators of body segmentation and cell growth, therefore being important players during development. PcG proteins form large complexes (PRC) that fulfil mostly repressive regulative functions on homeotic gene expression. Although expression of PcG genes in the brain has been noticed, the involvement of PcG genes in the processes of brain development is not understood. In this study, we analysed the expression patterns of PRC1 complex members to reveal PcG proteins that might be relevant for mouse brain development. Using in situ hybridisation, we show PRC1 activity in proliferative progenitor cells during neurogenesis, but also in maturated neuronal structures. PRC1 complex compositions vary in a spatial and temporal controlled manner during mouse brain development, providing cellular tools to act in different developmental contexts of cell proliferation, cell fate determination, and differentiation.
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http://dx.doi.org/10.1002/dvdy.20876DOI Listing
September 2006

Enhancement of antimicrobial effects by glucocorticoids.

Med Microbiol Immunol 2005 Jan 18;194(1-2):47-53. Epub 2003 Nov 18.

Institute for Medical Microbiology, Heinrich-Heine-University, Universitätsstrasse 1, Geb. 22.21, 40225, Düsseldorf, Germany.

In the past few years a body of evidence has accumulated showing that stimulation of human astrocytes and microvascular endothelial cells with IFN-gamma induces a potent antibacterial and anti-parasitic effect. We have found that the IFN-gamma-mediated activation of the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) is, at least in part, responsible for this antimicrobial activity. Glucocorticoids are frequently used in inflammatory central nervous system diseases to reduce the inflammatory reaction and cerebral edema. Since in many inflammatory conditions infection is either a primary or secondary factor, steroids are administered, in these circumstances, during infection. We investigated whether steroids could affect the antimicrobial effect of IFN-gamma-induced IDO activation. We found that hydrocortisone and dexamethasone enhance IFN-gamma-mediated IDO activity in both human astrocytoma cells and native human astrocytes. Furthermore, we found that the amounts of IDO mRNA and of IDO protein are enhanced in cells treated with IFN-gamma and glucocorticoids. In addition, we were able to demonstrate that both steroids enhance the IFN-gamma-mediated antimicrobial activity against Toxoplasma gondii, Staphylococcus aureus and group B streptococci. The enhanced antimicrobial effect of IFN-gamma in the presence of glucocorticoids is due to the enhancement of the IDO-mediated tryptophan degradation, demonstrated by the complete abrogation of this antimicrobial effect by tryptophan resupplementation. These data show that glucocorticoids, which were often used to inhibit proinflammatory processes, do not decrease IDO-mediated antimicrobial effects. In contrast, high doses of steroids were able to enhance the IFN-gamma-induced antimicrobial activity.
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http://dx.doi.org/10.1007/s00430-003-0210-1DOI Listing
January 2005