Institute of Molecular Animal Breeding and Biotechnology

München, Germany

Institute of Molecular Animal Breeding and Biotechnology

München, Germany
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Yen Y.-C.,Max Planck Institute of Psychiatry | Mauch C.P.,Max Planck Institute of Psychiatry | Dahlhoff M.,Institute of Molecular Animal Breeding and Biotechnology | Micale V.,Max Planck Institute of Psychiatry | And 5 more authors.
Neurobiology of Learning and Memory | Year: 2012

Patients diagnosed for anxiety disorders often display faster acquisition and slower extinction of learned fear. To gain further insights into the mechanisms underlying these phenomenona, we studied conditioned fear in mice originating form a bi-directional selective breeding approach, which is based on elevated plus-maze behavior and results in CD1-derived high (HAB), normal (NAB), and low (LAB) anxiety-related behavior mice. HAB mice displayed pronounced cued-conditioned fear compared to NAB/CD1 and LAB mice that coincided with increased phosphorylation of the protein kinase B (AKT) in the basolateral amygdala 45. min after conditioning. No similar changes were observed after non-associative immediate shock presentations. Fear extinction of recent but not older fear memories was preserved. However, HAB mice were more prone to relapse of conditioned fear with the passage of time. HAB mice also displayed higher levels of contextual fear compared to NAB and LAB mice and exaggerated avoidance following step-down avoidance training. Interestingly, HAB mice showed lower and LAB mice higher levels of acoustic startle responses compared to NAB controls. The increase in arousal observed in LAB mice coincided with the general absence of conditioned freezing. Taken together, our results suggest that the genetic predisposition to high anxiety-related behavior may increase the risk of forming traumatic memories, phobic-like fear and avoidance behavior following aversive encounters, with a clear bias towards passive coping styles. In contrast, genetic predisposition to low anxiety-related and high risk-taking behavior seems to be associated with an increase in active coping styles. Our data imply changes in AKT phosphorylation as a therapeutic target for the prevention of exaggerated fear memories. © 2012 Elsevier Inc.

Dahlhoff M.,Max Planck Institute of Psychiatry | Dahlhoff M.,Institute of Molecular Animal Breeding and Biotechnology | Siegmund A.,Max Planck Institute of Psychiatry | Golub Y.,Max Planck Institute of Psychiatry | And 4 more authors.
Neuroscience | Year: 2010

Only a small percentage of individuals develop posttraumatic stress disorder (PTSD) in the aftermath of a trauma. It is still largely unknown to what extent gene-environment interactions contribute to the inter-individual differences in PTSD susceptibility and resilience and what cellular processes may underlie long-term maintenance of the disorder. Here we employed a mouse model of PTSD to unravel the contribution of genetic background and maternal influences on long-lasting changes in kinase and transcription factor activities in PTSD-susceptible C57BL/6NCrl (B6N) and resilient C57BL/6JOlaHsd (B6JOla) mice. Mice received an inescapable foot shock and were tested for activity changes in the AKT/GSK-3β/β-catenin-pathway in specific brain structures 42 days later. To control for prenatal and postnatal environmental (i.e. maternal) factors part of the experiments were performed with animals originating from within-strain and between-strain embryo transfers. In PTSD-susceptible B6N mice, long-term maintenance of contextual and sensitized fear was accompanied by (i) increased levels of phosphorylated AKT within the dorsal hippocampus and (ii) higher levels of phosphorylated AKT and GSK-3β and increased β-catenin levels within the basolateral amygdala. In animals originating from embryo transfers, levels of phosphorylated GSK-3β and of β-catenin were decreased in the dorsal hippocampus, but increased in the basolateral amygdala of shocked B6N mice compared to shocked B6JOla mice. This was independent of the genotype of the recipient mothers. At the behavioural level, these differences coincided with sustained sensitized and more pronounced contextual fear of B6N compared to B6JOla mice. Taken together our study identifies lasting changes in the AKT/GSK-3β/β-catenin cascade within the hippocampus and amygdala as molecular correlates of genetically determined differences in the severity of PTSD-like symptoms. © 2010 IBRO.

Dahlhoff M.,Institute of Molecular Animal Breeding and Biotechnology | Algul H.,TU Munich | Siveke J.T.,TU Munich | Lesina M.,TU Munich | And 6 more authors.
Gastroenterology | Year: 2010

Background & Aims: Acute pancreatitis (AP) is a serious, unpredictable clinical problem, the pathophysiology of which is poorly understood. Here, we evaluate whether betacellulin (BTC), a ligand of the epidermal growth factor receptor also able to activate the proapoptotic ERBB4 receptor, can protect against experimental AP. Methods: AP was induced in transgenic mice overexpressing BTC (BTC-tg), control mice, or control mice after administration of recombinant BTC. The severity of pancreatitis was assessed by measurements of serum amylase and lipase and histologic grading. The involvement of the stress-activated protein kinase (SAPK) was evaluated by treating BTC-tg mice with an SAPK inhibitor before induction of AP. Results: BTC-tg mice showed increased apoptosis and proliferation in the exocrine pancreas, indicating an increased cell turnover. There was a marked, epidermal growth factor receptor-independent decrease in pancreas weight. After induction of AP by cerulein injection, BTC-tg mice showed a significantly lower increase in serum amylase and lipase levels as well as less pronounced tissue necrosis, edema, and inflammation, as compared to nontransgenic littermates. This protective effect, also confirmed in the l-arginine AP model, was associated with increased phosphorylation of SAPK and abrogated after treatment of BTC-tg mice with a SAPK inhibitor. Finally, the protective effect of BTC against AP was confirmed by treating nontransgenic mice with recombinant BTC. Conclusions: These findings indicate a potential application of the BTC/ERBB4 pathway for modulating the course of AP. © 2010 AGA Institute.

Schafer M.,Institute of Molecular Health science | Willrodt A.-H.,Institute of Molecular Health science | Kurinna S.,Institute of Molecular Health science | Link A.S.,Friedrich - Alexander - University, Erlangen - Nuremberg | And 14 more authors.
EMBO Molecular Medicine | Year: 2014

The transcription factor Nrf2 is a key regulator of the cellular stress response, and pharmacological Nrf2 activation is a promising strategy for skin protection and cancer prevention. We show here that prolonged Nrf2 activation in keratinocytes causes sebaceous gland enlargement and seborrhea in mice due to upregulation of the growth factor epigen, which we identified as a novel Nrf2 target. This was accompanied by thickening and hyperkeratosis of hair follicle infundibula. These abnormalities caused dilatation of infundibula, hair loss, and cyst development upon aging. Upregulation of epigen, secretory leukocyte peptidase inhibitor (Slpi), and small proline-rich protein 2d (Sprr2d) in hair follicles was identified as the likely cause of infundibular acanthosis, hyperkeratosis, and cyst formation. These alterations were highly reminiscent to the phenotype of chloracne/"metabolizing acquired dioxin-induced skin hamartomas" (MADISH) patients. Indeed, SLPI, SPRR2, and epigen were strongly expressed in cysts of MADISH patients and upregulated by dioxin in human keratinocytes in an NRF2-dependent manner. These results identify novel Nrf2 activities in the pilosebaceous unit and point to a role of NRF2 in MADISH pathogenesis. © 2014 The Authors.

Dahlhoff M.,Institute of Molecular Animal Breeding and Biotechnology | Rose C.,University of Lübeck | De Angelis M.H.,Helmholtz Center for Environmental Research | De Angelis M.H.,TU Munich | And 2 more authors.
American Journal of Pathology | Year: 2012

The negative feedback regulation of epidermal growth factor receptor (EGFR) and other tyrosine kinase receptors, including receptor dephosphorylation and endocytosis followed by degradation, is becoming recognized as a major determinant of receptor function. To evaluate the significance of the negative regulation of EGFR during carcinogenesis in vivo, we subjected the mutant mouse line Dsk5, in which the intrinsic activation of the receptor due to a point mutation is normally counterbalanced by increased posttranslational receptor down-regulation, to skin chemical carcinogenesis. Dsk5 mice showed reduced tumor numbers and tumor burden compared with control littermates, and Dsk5-derived tumors showed a reduction in the activation and total levels of EGFR. Furthermore, the transcript levels of several molecules known to act as negative regulators of EGFR were significantly increased in Dsk5-derived tumors. Another intriguing observation was the appearance of tumors with sebaceous differentiation in the ears of Dsk5 mice after chemical carcinogenesis. Further studies are necessary to reveal whether these tumors represent a cell typespecific evasion from EGFR negative feedback machinery. In conclusion, this study reveals that several negative feedback regulators contribute to suppression of the intrinsic activation of mutant EGFR during skin carcinogenesis, stressing the potential exploitation of negative regulators as either therapeutic targets or diagnostic tools in cancer and other diseases. © 2012 American Society for Investigative Pathology.

Dahlhoff M.,Institute of Molecular Animal Breeding and Biotechnology | Frohlich T.,Gene Center | Arnold G.J.,Gene Center | Muller U.,Human Biology and BioImaging | And 3 more authors.
Experimental Cell Research | Year: 2015

Lipid metabolism depends on lipid droplets (LD), cytoplasmic structures surrounded by a protein-rich phospholipid monolayer. Although lipid synthesis is the hallmark of sebaceous gland cell differentiation, the LD-associated proteins of sebocytes have not been evaluated systematically.The LD fraction of SZ95 sebocytes was collected by density gradient centrifugation and associated proteins were analyzed by nanoliquid chromatography/tandem mass spectrometry. 54 proteins were significantly enriched in LD fractions, and 6 of them have not been detected previously in LDs. LD fractions contained high levels of typical LD-associated proteins as PLIN2/PLIN3, and most proteins belonged to functional categories characteristic for LD-associated proteins, indicating a reliable dataset. After confirming expression of transcripts encoding the six previously unidentified proteins by qRT-PCR in SZ95 sebocytes and in another sebocyte line (SebE6E7), we focused on two of these proteins, ALDH1A3 and EPHX4. While EPHX4 was localized almost exclusively on the surface of LDs, ALDH1A3 showed a more widespread localization that included additional cytoplasmic structures. siRNA-mediated downregulation revealed that depletion of EPHX4 increases LD size and sebaceous lipogenesis. Further studies on the roles of these proteins in sebocyte physiology and sebaceous lipogenesis may indicate novel strategies for the therapy of sebaceous gland-associated diseases such as acne. © 2014 Elsevier Inc.

Dahlhoff M.,Institute of Molecular Animal Breeding and Biotechnology | de Angelis M.H.,Helmholtz Center for Environmental Research | de Angelis M.H.,TU Munich | Wolf E.,Institute of Molecular Animal Breeding and Biotechnology | Schneider M.R.,Institute of Molecular Animal Breeding and Biotechnology
Experimental Dermatology | Year: 2013

The epidermal growth factor receptor (EGFR) system is an established regulator of the development and homeostasis of the hair follicle and interfollicular epidermis. Here, we evaluated EGFR actions on the sebaceous glands (SGs) by employing Dsk5 mice, a mutant line in which the EGFR is constitutively activated in a ligand-independent manner. Compared to control littermates, Dsk5 mice showed increased sebum levels and enlarged SGs, which contained a higher number of cells and showed stronger proliferation. c-myc transcript levels were increased in Dsk5 skin, suggesting that c-myc mediates the proliferative stimuli of the EGFR in the SG. Analysis of differentiation markers revealed deregulated expression of Scd1 and Scd3, indicating that sebaceous lipogenesis is affected in Dsk5 mice. In conclusion, our study indicates that the EGFR is an important regulator of presebocyte proliferation, contributing to the final cell number, to the size and to the lipid output of SGs. © 2013 John Wiley & Sons A/S.

Thoeringer C.K.,Max Planck Institute of Psychiatry | Henes K.,Max Planck Institute of Psychiatry | Eder M.,Max Planck Institute of Psychiatry | Dahlhoff M.,Institute of Molecular Animal Breeding and Biotechnology | And 5 more authors.
Neuropsychopharmacology | Year: 2012

Persistent dreadful memories and hyperarousal constitute prominent psychopathological features of posttraumatic stress disorder (PTSD). Here, we used a contextual fear conditioning paradigm to demonstrate that conditional genetic deletion of corticotropin-releasing hormone (CRH) receptor 1 within the limbic forebrain in mice significantly reduced remote, but not recent, associative and non-associative fear memories. Per os treatment with the selective CRHR1 antagonist DMP696 (3 mg/kg) attenuated consolidation of remote fear memories, without affecting their expression and retention. This could be achieved, if DMP696 was administered for 1 week starting as late as 24 h after foot shock. Furthermore, by combining electrophysiological recordings and western blot analyses, we demonstrate a delayed-onset and long-lasting increase in AMPA receptor (AMPAR) GluR1-mediated signaling in the dentate gyrus (DG) of the dorsal hippocampus 1 month after foot shock. These changes were absent from CRHR1-deficient mice and after DMP696 treatment. Inactivation of hippocampal GluR1-containing AMPARs by antisense oligonucleotides or philantotoxin 433 confirmed the behavioral relevance of AMPA-type glutamatergic neurotransmission in maintaining the high levels of remote fear in shocked mice with intact CRHR1 signaling. We conclude that limbic CRHR1 receptors enhance the consolidation of remote fear memories in the first week after foot shock by increasing the expression of Ca 2+-permeable GluR1-containing AMPARs in the DG. These findings suggest both receptors as rational targets for the prevention and therapy, respectively, of psychopathology associated with exaggerated fear memories, such as PTSD. © 2012 American College of Neuropsychopharmacology. All rights reserved.

Schneider M.R.,Institute of Molecular Animal Breeding and Biotechnology | Kolligs F.T.,Ludwig Maximilians University of Munich
BioEssays | Year: 2015

Recent studies uncovered critical roles of the adhesion protein E-cadherin in health and disease. Global inactivation of Cdh1, the gene encoding E-cadherin in mice, results in early embryonic lethality due to an inability to form the trophectodermal epithelium. To unravel E-cadherin's functions beyond development, numerous mouse lines with tissue-specific disruption of Cdh1 have been generated. The consequences of E-cadherin loss showed great variability depending on the tissue in question, ranging from nearly undetectable changes to a complete loss of tissue structure and function. This review focuses on these studies and discusses how they provided important insights into E-cadherin's role in cell adhesion, proliferation and differentiation, and its consequences for biological processes as epithelial-to-mesenchymal transition, vascularization, and carcinogenesis. Lastly, we present some perspectives and possible approaches for future research. © 2015 WILEY Periodicals, Inc.

Dahlhoff M.,Institute of Molecular Animal Breeding and Biotechnology | Gerhard M.,TU Munich | Rad R.,TU Munich | Linden S.,Gothenburg University | And 2 more authors.
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2012

Hyperactivation of the epidermal growth factor receptor (EGFR) in gastric cells due to excess of its ligand transforming growth factor-α (TGFA) is associated with hyperplastic lesions in Ménétrier's disease patients and in transgenic mice. Other EGFR ligands, however, have never been associated with stomach diseases. Here, we report that overexpression of the EGFR ligand betacellulin (BTC) results in a severe, age-dependent hyperplasia of foveolar epithelium. The stomach weight of affected mice reached up to 3g representing more than 10% of total body weight. The preexisting corpus mucosa was severely depleted, and both parietal and chief cells were replaced by proliferating foveolar epithelium. The lesions were more severe in male as compared to female transgenic mice, and partially regressed in the former after castration-mediated androgen removal. The gastric hyperplasia fully disappeared when BTC-tg mice were crossed into the EgfrWa5 background expressing a dominant-negative EGFR, indicating that the phenotype is EGFR-dependent. This is, to our knowledge, the first report of hyperplastic gastric lesions due to the overexpression of an EGFR ligand other than TGFA. BTC-tg mice are therefore a new, promising model for studying EGFR-dependent gastric polyps. © 2012 Elsevier B.V.

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