MausDB: The German Mouse Clinic open source phenotype- and mouse management system.

Mutant mouse lines are important tools to elucidate gene function as observed phenotypes can mostly be attributed to a known genotype. The German Mouse Clinic (GMC, http://www.mouseclinic.de) as an open-access platform offers standardized and comprehensive phenotype analysis of mutant mouse lines and screens for potential new mouse models of human diseases. In the GMC, mouse cohorts pass through 14 different screening modules in a strictly defined workflow in the course of primary screen where up to 240 physiological parameters per mouse are measured. Screening many mouse cohorts in multi-parallel workflows is a logistical challenge and requires appropriate IT support and well-defined data infrastructure. Therefore, we developed a web-based database application – MausDB – for the GMC that serves as a central data platform accessible by all GMC users. MausDB supports scheduling of mouse lines to the phenotyping pipelines by work list management functions. Phenotyping data upload to MausDB and re-export is done via spreadsheet files. MausDB also offers standard mouse management functions (breeding support, cage management, etc.) and integrates phenotype data with line/genotype data and other metadata on the individual mouse level. For the GMC, this is a prerequisite for inter-line data analysis, data mining and data exchange in a cross-European phenotyping effort (EUMODIC). Although primarily developed for the GMC, MausDB also proved to be useful for other mouse facilities due to its general purpose design and intuitive user interface. Hence, we offer MausDB to the mouse community as open source software under the terms of the GNU General Public License

The German mouse clinic: A platform for systemic phenotype analysis of mouse models

The German Mouse Clinic (GMC) is a large scale phenotyping center where mouse mutant lines are analyzed in a standardized and comprehensive way. The result is an almost complete picture of the phenotype of a mouse mutant line - a systemic view. At the GMC, expert scientists from various fields of mouse research work in close cooperation with clinicians side by side at one location. The phenotype screens comprise the following areas: allergy, behavior, clinical chemistry, cardiovascular analyses, dysmorphology, bone and cartilage, energy metabolism, eye and vision, hostpathogen interactions, immunology, lung function, molecular phenotyping, neurology, nociception, steroid metabolism, and pathology. The German Mouse Clinic is an open access platform that offers a collaboration-based phenotyping to the scientific community (www.mouseclinic.de). More than 80 mutant lines have been analyzed in a primary screen for 320 parameters, and for 95% of the mutant lines we have found new or additional phenotypes that were not associated with the mouse line before. Our data contributed to the association of mutant mouse lines to the corresponding human disease. In addition, the systemic phenotype analysis accounts for pleiotropic gene functions and refines previous phenotypic characterizations. This is an important basis for the analysis of underlying disease mechanisms. We are currently setting up a platform that will include environmental challenge tests to decipher genome-environmental interactions in the areas nutrition, exercise, air, stress and infection with different standardized experiments. This will help us to identify genetic predispositions as susceptibility factors for environmental influences

Misassembly of full-length Disrupted-in-Schizophrenia 1 protein is linked to altered dopamine homeostasis and behavioral deficits

Disrupted-in-schizophrenia 1 (DISC1) is a mental illness gene first identified in a Scottish pedigree. So far, DISC1-dependent phenotypes in animal models have been confined to expressing mutant DISC1. Here we investigated how pathology of full-length DISC1 protein could be a major mechanism in sporadic mental illness. We demonstrate that a novel transgenic rat model, modestly overexpressing the full-length DISC1 transgene, showed phenotypes consistent with a significant role of DISC1 misassembly in mental illness. The tgDISC1 rat displayed mainly perinuclear DISC1 aggregates in neurons. Furthermore, the tgDISC1 rat showed a robust signature of behavioral phenotypes that includes amphetamine supersensitivity, hyperexploratory behavior and rotarod deficits, all pointing to changes in dopamine (DA) neurotransmission. To understand the etiology of the behavioral deficits, we undertook a series of molecular studies in the dorsal striatum of tgDISC1 rats. We observed an 80% increase in high-affinity DA D2 receptors, an increased translocation of the dopamine transporter to the plasma membrane and a corresponding increase in DA inflow as observed by cyclic voltammetry. A reciprocal relationship between DISC1 protein assembly and DA homeostasis was corroborated by in vitro studies. Elevated cytosolic dopamine caused an increase in DISC1 multimerization, insolubility and complexing with the dopamine transporter, suggesting a physiological mechanism linking DISC1 assembly and dopamine homeostasis. DISC1 protein pathology and its interaction with dopamine homeostasis is a novel cellular mechanism that is relevant for behavioral control and may have a role in mental illness