The

German Mouse Clinic

Helmut Fuchs,

and the GMC-Consortium

Helmholtz Zentrum München Institute of Experimental Genetics

The 2 strategies: BU and TD

Bottom up

Top down

Requests from the scientific comunity

Bilateral collaborations

Centrally organized projects

• offers systemic phenotypic analysis of mouse mutants

on the basis of scientific collaboration

• Runs a primary screening of more than 500 parameters

in 14 different screens

• offers detailed analysis in secondary screening

• GMC II genome meets environment

• GMC III Systemic analysis of compound and drug action

The German Mouse Clinic

• Open access

• logistics developed for open access of scientific community

• experts from different research areas work together in one

facility (consortium)

• systemic interpretation of results

Unique concept

Selection: Nat Med (2005, 2012, 2015), Nat Com 2014, Hum Mol Genet(2012, 2014), EMBO J (2010, 2014), BBRC (2013), Development (2013),

Acta Neuropathol (2012), Nucleic Acids Res (2010, 2014). PLoS Genet (2012, 2014), PLoS Biol (2010), Blood (2011), Bone (2013), Histol

Histopath (2013), J Cell Science (2011), J Biol Chem (2011, 2013), Methods (2011), Faseb J (2012), Eur J Endocrinol (2012), J Comp Neurol

(2012), Science (2010), BMC Neurosci (2012), (Diabetes 2015), Nat Genet (2015,2016) JCI (2013)

Age [weeks] 7 8 9 10 11 12 13 14 15 16

Screens Methods

Behaviour Open field

Acoustic startle response & PPI

Neurology Modified SHIRPA, grip strength

Rotarod

Dysmorphology Anatomical observation

Energy Metabolism Indirect calorimetry

Cardiovascular Awake ECG / Echocardiography

Clinical Chemistry IpGTT

Neurology ABR (Auditory brain stem response)

Dysmorphology X-ray, DEXA

Nociception Hotplate

Eye Scheimpflug imaging, OCT, LIB, drum

Clinical Chemistry Clinical Chemical analysis, hematology

Immunology FACS analysis of PBCs

Allergy BIOPLEX ELISA (Ig concentration)

Pathology Macro & microscopic analysis

Molecular Phenotyping (optional) Expression profiling

B) Pipeline anxiety, depression or schizophrenia

A 4

Acoustic

startle&P

PI

A1 Open

field

B2

Elevated

plus maze

B2 Social

interaction

B4

Swimabilit

y test

B5 Tail

suspensi

on

B1 Light/

dark box

B6 Acute

stress

C) Pipeline learning and memory

D) Pipeline motoric abilities

A5

Rotarod

A3

SHIRPA

D2

Ladder

walk

D3

Vertical

pole

D4

Inverted

grid

D1 Beam

walk

D5 Gait

analysis

E) Pipeline sensoric abilities

A20 ABR A7 Hot

plate

E2

Electro-

retino-

gram

E3. nerve

conduc-

tance

E4

Seizures

E1 Eye

pressure E5 EEG

Pipelines for secondary analyses

Behaviour and Neurology

C2 Social

discrimina

tion

C1 Y-

maze

C4

Intellicage

C5 Olfakt.

discrimina

tion

C6 Neuro-

genesis

C3 Object

recogni-

tion

C7 pharm.

Antagon.

F) Pipeline kidney function

G) Pipeline glucose metabolism

A5 Blood sample A11 Body composition

(NMR)

A12 Glucose

tolerance test

G1 Insuline

tolerance Test

A5 Blood

sample

G2 Glucose-

Clamp

A5 Blood

sample F1 Analysis of kidney function A21 Histo-pathology

H) Pipeline energy metabolism

I) Pipeline non-invasive imaging technologies

I2 MRI I1 Micro CT

Physiology, energy metabolism and diabetes

A5 Blood

sample

A11 Body

composition(NM

R)

H2 Energy

balance

H3 Breath

gas analysis

A5 Blood

sample

A10 Ind.

calorimetry

H4 Cold

challenge

H1

Implantation

of sensor

Pipelines for secondary analyses

MRT-Applications

• Brain imaging

• Heart imaging

• Knee joint

• Body composition

• Liver spectroscopy

Immunology, Allergy and lung diseases

M) Analysis of progressive phenotypes

Repetition of special analyses

J) Pipeline Immunity

K) Pipeline Allergy

L) Pipeline lung function: Either Acute lung injury test, Elastase-induced lung-emphysem, Cigarette induced lung-emphysem or bleomycin-induced lung-fibrosis

L Lung function

analysis

K1

OVA

sensitation

K2

OVA aerosol

provocation

K3

Blood sample and

histo-pathology

A5

Blood sample

J1 Primary

infection

resistence

J2

T-cell

response

J3

Protective

immunity

A5

Blood sample

J4

Inflammation-

test

Pipelines for secondary analyses

• sensimotor neurological disorder • urge to move the legs • symptoms occur exclusively during rest, evening and

night • Age – dependent prevalence of up to 10% in

western societies

• GWAS identified Meis 1 (homeobox transcription factor (TALE family)) locus for Restless Legs Syndrome (RLS)

• SNP in risk allele of MEIS1 highly conserved non-coding

region (intron 8)

• Leads to reduced gene expression in the future basal ganglia in the forebrain - pathophysiology of RLS includes aspects of neurodevelopmental disorders

Disease model Restless Legs Syndrome (RLS)

Spieler et al., 2014 Genome Research

Motor restlessness/hyperactivity in adult heterozygous Meis1tm1Mtormice

7

Systemic phenotyping of mice with

reduced Meis 1 expression revealed

motor restlessness and hyperactivity

Behavior Screen:

• Alteration of the behavior

phenotype towards hyperactive

locomotion in a novel

environment (Open Field)

Metabolic Screen:

• Hyperactivity in home cage

conditions and increased energy

expenditure (Indirect Calorimetry)

Spieler et al., 2014 Genome Research

http://www.mouseclinic.de/

Publically available phenotyping data

Phenomap

16

Reporting • GMC phenomap • Bottom-up projects: PDF-reports

MausDB – reporting

Standardized Mouse Phenotyping

Envirotype “Challenge” Tests

Systemic Analysis of Compounds & Drugs

Envirotypes

Beckers et al. Nature Reviews Genetics 2009

air stress

immunity/ inflammation

nutrition, diet

exercise physical activity

envirotype platforms

Tread-mill Jump

exercise

Infection Challenge Allergen exposure

Light exposure Restraint Oxidative

stress

High fat diet fasting

Instillation of diesel particles

Standardized challenge tests and their combination

The 2 strategies: BU and TD

Bottom up

Top down

Requests from the scientific comunity

Bilateral collaborations

Centrally organized projects

Hrabě de Angelis…. Brown

Nature Genetics 2015

New phenotypes revealed – genes with no prior annotations

www.mousephenotype.org

IMPC activities • Undertake broad-based phenotyping of 20,000 mutants

(genes) from the IKMC resource

• Phase 1 (2011-2016): Phenotype up to 5,000 lines

• Phase 2 (2016-2021): Phenotype 15,000 lines

• Data freely available through a Data Coordination Centre

• Mice available through the global network of mouse

repositories

IMPC pipeline

IMPC phenoview

6

www.infrafrontier.eu

INFRAFRONTIER – Access to mammalian

models for biomedical research Pan-European Research Infrastructure

How to contact us?

Neurology Lore Becker Ingrid Vargas P. Thomas Klopstock IEG, HMGU/LMU München Allergy Juan Antonio Aguilar-Pimentel Carsten Schmidt-Weber Markus Ollert IEG, HMGU/TU München/Institute of Health Luxembourg/University of Southern Denmark Bioinformatics/Statistics Manuela Östereicher Anja Hurt Christine Schütt Ralf Schneider Elida Schneltzer Ralf Steinkamp Karlheinz Schäble Christoph Lengger Holger Maier IEG, HMGU Mouse production Susan Marschall and team Andreas Hörlein and team Ralf Kühn and team IEG/IDG, HMGU

Martin Hrabě de Angelis (Director) Valérie Gailus-Durner (Scientific Administrative Head) GMC Management Team Claudia Stöger Stefanie Leuchtenberger Christine Hutterer Sandra Greißel Cindy Gonda IEG, HMGU Behavior Sabine M. Hölter Lillian Garrett Annemarie Zimprich Wolfgang Wurst IDG, HMGU Dysmorphology Robert Brommage Martin Hrabě de Angelis IEG, HMGU Diabetes Jan Rozman Martin Hrabě de Angelis IEG, HMGU

Clinical Chemistry Birgit Rathkolb Eckhard Wolf LMU München Immunology Irina Treise Dirk H. Busch IEG, HMGU/TU München Cardiovascular Kristin Moreth Raffi Bekeredjian Hugo A. Katus IEG, HMGU/University of Heidelberg Pathology Julia Calzada-Wack Pathology, HMGU Lung Function Tobias Stöger Ali Önder Yildirim Oliver Eickelberg iLBD, HMGU

Energy Metabolism Jan Rozman Monja Willershäuser Martin Kistler Martin Klingenspor IEG, HMGU/TU München Steroid Metabolism Cornelia Prehn Gabriele Möller Jerzy Adamski IEG, HMGU Eye Oana Amarie Jochen Graw IDG, HMGU Nociception Lore Becker Andreas Zimmer IEG/HMGU, University of Bonn Molecular Phenotyping Johannes Beckers IEG, HMGU Infrafrontier Michael Räß IEG, HMGU

Thanks to