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Development and Growth disorders are usually investigated for lethal or subviable mutations; this occurs for 24% and 10% of the genes, respectively (IMPC data). These genes are of special interest for both developmental biologists and clinicians as they are potential candidates for human developmental disorders and rare genetic diseases.

New tests

Embryo analysis by HREM

Suggested primary analysis

See our Anatomopathology dedicated page to explore all our available tests.

Purpose

Cell death by apoptosis can be investigated in ex vivo sections by TUNEL staining (Terminal deoxynucleotidyl transferase-mediated dUTP Nick End Labeling) and/or cleaved caspase 3 immunohistochemistry.  TUNEL represents the standard assay for detecting apoptotic cells on histological sections.

Anapth_apoptosis_1.pngApoptotic granulosa cells (green dots) in atretic ovarian follicles

Recommendations

When comparing apoptosis between different tissues, all samples are fixed and processed under the same conditions. At least, 3 mutant mice versus 3 littermate control mice are required for relevant results.

Purpose

Tissue cell proliferation markers provide information on cell cycle progression with BrdU as an indicator of cells having passed through S-phase, phospho-H3 for cells in M-phase, and Ki67 for actively cycling cells.

  • BrdU incorporation detects cells in S phase 
  • anti-Ki 67 immunohistochemistry detects cells which are in the cell cycle and distinguishes them from quiescent cells 
  • phosphorylated histone H3 marks mitotic cells and is detectable by immunohistochemistry.

Anapath_CellProliferation_1Detection of BrdU incorporation in seminiferous tubules: positive cells are confined to the periphery of the tubules and correspond to spermatogonia and preleptotene spermatocytes close

Anapath_CellProliferation_2.pngImmunoperoxidase staining for detection of phosphorylated histone H3. Ventral prostate. Negative image obtained by Photoshop® processing of the original, dark-field, pictures. The labeled cell is in metaphase.

Anapath_CellProliferation_3.pngImmunoperoxydase staining for detection of the Ki67 (left panels) and DAPI counterstain (right panels). Stages VII (top two panels) and X (bottom panels) of the seminiferous epithelium cycle.

 

Purpose

To better characterize the primary defects of the mutants, vascular (PECAM), neural (neruofilament), endodermal (HNF3b) markers are proposed. Other marker stainings can be developed on demand.

Embryo analysis

Purpose

HREM is an effective and powerful tool for assessing structural abnormalities in embryos. Three dimensional reconstruction of embryo slices provides the definition of histological staining with the completeness of 3-D imaging.

Equipment

HREM imaging is operated with a home made system (developed with the IGBMC Imaging Center)

Anapath_EmbryoAnalysis_HREM equipment.png

 

Sample processing

1-The sample is fixed in Bouin’s solution  

2-JB4 Resin embedding :

  • Ethanol dehydration
  • Resin infiltration
  • Resin polymerisation
  • Bloc drying
  • Bloc storage

3-Samples limitations: the size must not exceed 1.5 cm3

Sample results

Imaging_HREM Embryos.png

Imaging-HREM-Embryos Organs.png

Recommendation

It is recommended to use at least 3 experimental and 3 control samples for analyse.

Purpose

Rapid three dimensional imaging of density-contrasted tissues (soft tissues) and non-contrasted tissues (skeletal elements) in the embryo using X-ray transmission and computed tomography.

Equipment

Anapath-MicroCT-800.png

Sample results :

  • MicroCT imaging of E18.5 fetuses

The phenotyping of fetuses at later stages (E18.5) can use micron-scale X-rays Computed Tomography (μCT), which achieves a resolution of 10μm (isotropic voxel size) and allows the morphological analysis of organs in situ without dissection. To achieve sufficient contrast, formalin-fixed fetuses will be stained in Lugol’s iodine as a contrast agent. The impregnation of iodine in tissues will increase X-rays absorption due to iodine’s high atomic number and therefore enhance contrast in the resulting images. Obtained raw data have to be processed to facilitate direct comparison between samples.

Imaging-EmbryoAnalysisbyMicroCT.png

Recommendation

It is recommended to use at least 3 experimental embryos and one control embryo for analyse.

Purpose

Sampling of embryos for viability at times throughout pregnancy with focus on development of particular organs between E9.5 and E18.5.

Anapath_EmbryoViability.pngDetermination of the window of lethality

Purpose

Embryonic growth restriction can be indicative of placental abnormalities. Macroscopical and routine histological analysis (hematoxylin & eosin) are performed to evaluate placental defects. 

X-Ray imaging

Purpose

Rapid three dimensional imaging of density-contrasted tissues (soft tissues) and non-contrasted tissues (skeletal elements) in the embryo using X-ray transmission and computed tomography.

Equipment

Anapath-MicroCT-800.png

Sample results :

  • MicroCT imaging of E18.5 fetuses

The phenotyping of fetuses at later stages (E18.5) can use micron-scale X-rays Computed Tomography (μCT), which achieves a resolution of 10μm (isotropic voxel size) and allows the morphological analysis of organs in situ without dissection. To achieve sufficient contrast, formalin-fixed fetuses will be stained in Lugol’s iodine as a contrast agent. The impregnation of iodine in tissues will increase X-rays absorption due to iodine’s high atomic number and therefore enhance contrast in the resulting images. Obtained raw data have to be processed to facilitate direct comparison between samples.

Imaging-EmbryoAnalysisbyMicroCT.png

Recommendation

It is recommended to use at least 3 experimental embryos and one control embryo for analyse.

Suggested secondary analysis

Purpose

The measurement of various blood metabolites, ions, and enzymes provides a primary screen for  function of major metabolic organs such as kidney, liver, gastrointestinal tract, as well as for lipid and glucose homeostasis. 

A panel of parameters is proposed, including:

  • Electrolytes and ions: Sodium (Na), Potassium (K), Chloride (Cl), Calcium (Ca), Magnesium (Mg), Phosphate (PO4), iron (Fe), and bicarbonate (CO2).
  • Enzymatic activities: Alpha-amylase, aspartate amino transaminase (AST), alanine amino transaminase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), lipase, creatine kinase (CK).
  • Metabolites: glucose, urea, creatinine, uric acid, total proteins, albumin, total bilirubin, triglycerides, free fatty acids, glycerol, total, HDL and LDL cholesterol, fructosamine, ketone bodies (B-HBA), transferrin, ferritin.

Biochem_Clinical Chemistry graph.jpg

Selected plasma chemistry data from female mice (N=20 per line) of common laboratory strains at different ages (Champy et al. Mammalian Genome 2008).  Error bars reflect ± SEM.

Equipment

These tests are performed with an AU-480 automated laboratory work station (Beckman Coulter France SAS, Villepinte, France).

Strain background references

Champy MF, Selloum M, Zeitler V, Caradec C, Jung B, Rousseau S, Pouilly L, Sorg T, Auwerx J. Genetic background determines metabolic phenotypes in the mouse. Mamm Genome. 2008 May;19(5):318-31. Epub 2008 Apr 5.

Purpose

Body composition for fat, lean and free body fluid is evaluated on conscious mice by quantitative nuclear magnetic resonance on Minispec analyzer.

Metabo_Body composition by qNMR graph

Body composition analysis of male mice from different common laboratory strains after provision of chow diet (CD) or 10 weeks provision of high-fat diet (HFD), including complete body weight, fat tissue content, and lean tissue content.  Dramatic increases in fat tissue is seen upon HFD-diet treatment for most strains excepting BALB/c, consistent with what has previously been reported. 

Equipment

Metabo_Body composition Equipement picture

Body composition is evaluated by Quantitative Nuclear Magnetic Resonance (qNMR) using Minispec+ analyzer (Bruker BioSpin S.A.S., Wissembourg, France)

Purpose

First-line hematological/immunological analysis of blood or tissue infiltrates for different leukocyte lineages. May be targeted to examine particular immune lineage subclasses.

Exemples:

Thymus: 

  • T cells of ab lineage: CD4/CD8/TCRab 
  • T cells of gd lineage: CD4/CD8/TCRgd 
  • NKT cells: NK1.1/CD3 

Spleen: 

  • B cells: CD19/IgM/IgD/CD80 
  • B cells: CD19/IgM/CD2/CD23 
  • NK cells and NKT cells: DX5/NK1.1/CD3 
  • Macrophages and neutrophils: F4-80/Gr-1/Mac-1 
  • T cells: CD4/CD8/CD3/CD44

Blood:

  • B cell: CD19/mature B cells IgD
  • Granulocyte
  • Monocyte
  • NK cell 
  • T cell : CD3/CD4/CD8
  • Treg cell : CD25

Please see our Immunology dedicated page for more detailed tests.

Equipment

FACS analysis are performed on a LSR II (BD diagnostics, Le pont de Claix, France).

See our Gene expression analysis dedicated page to explore our different related tests.

See our In vivo Viral Transduction dedicated page to explore our frequently used vectors and delivery modes including stereotactic admininistration (intraventricular and cerebellar)

 

Food challenge

Purpose

With several months notice, we can procure and provide a variety of different restriction diets for nutritional analyses in conjuction with our other analyses.

Ultrasounds imaging

X-Ray imaging

Purpose

The X-Ray system gives very precise images of the skeletton. In DXA mode it automatically calculates BMD, BMC, and lean and fat mass percentages.

Strain background references

Champy MF, Selloum M, Zeitler V, Caradec C, Jung B, Rousseau S, Pouilly L, Sorg T, Auwerx J. 
Genetic background determines metabolic phenotypes in the mouse. 
Mamm Genome. 2008 May;19(5):318-31. Epub 2008 Apr 5.

Equipment 

Imaging_Bone mineral density equipment DEXA

pDEXA Sabre (Norland)

Sample data

Imaging_Bone mineral density image DEXA

Recommendations

  • For performance in conjunction with X-ray analysis.
  • 8 mice per group are recommended for reliable data analysis.

Models and Challenges

Purpose

With several months notice, we can procure and provide a variety of different restriction diets for nutritional analyses in conjuction with our other analyses.

See our In vivo Viral Transduction dedicated page to explore our frequently used vectors and delivery modes including stereotactic admininistration (intraventricular and cerebellar)