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Tissue-specific KO mouse
Mouse model generation

Tissue-specific KO mouse

Use tissue- or cell-specific conditional Knockout mouse models to bypass embryonic lethality, compensatory mechanisms, complex phenotypes, etc.

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A tissue-specific Knockout mouse defines an animal model in which a gene of interest is "floxed" and thus inactivatable in specific cell types in a certain tissue (conditional). Other cell types and tissues exhibit an unmodified, functional gene expression.

This gene inactivation is achieved by an additional breeding step with a tissue- or cell type-specific Cre-deleter mouse line. Such models also give access to whole body (constitutive) Knockouts.

Applications

For academic research:

  • Study gene function in one specific organ, tissue or cell type
  • Mimic pathologies caused by gene inactivation or deficiency in a given cell type
  • Create a tissue-specific phenotype for multi-function proteins

For bio-pharmaceutical research & development:

  • Validate target genes with cell-specific functions
  • Investigate signaling pathways in certain cell types
  • Safety studies

Strengths of tissue-specific Knockout mouse models

  • Very flexible: easy switch to study another tissue
  • Large resource of deleter mice (Cre or FLP), enabling an almost infinite combination of tissue-specificities
  • High physiological relevancy of the obtained scientific data from such a model
  • Enables access as well to constitutive Knockout for comparison studies

Limitations of tissue-specific Knockout mouse models

  • Mouse line creation requires the insertion of exogenous sequences (lox, FRT) that can deregulate transcription and splicing
    → Risk can be greatly minimized by applying in-depth bio-informatic, genetic, and bibliographic analysis
  • Inactivation of the gene of interest in one cell type may occur during cell type differentiation, resulting in an impaired phenotype and/or modified cell physiology
    →  Limitation can be bypassed by applying conditions such as time-specific gene inactivation
  • To obtain tissue specificity, a crossing step with a deleter mouse line implies a time-consuming production of cohorts
    →  This "time" issue must be anticipated and integrated in the scientific consulting prior to model development

Case study

Model for Crohn’s disease (CD)

Tschurtschenthaler M, et al. Defective ATG16L1-mediated removal of IRE1α drives Crohn's disease-like ileitis. J Exp Med. 2017.

ATG16L1T300A, a major risk polymorphism in CD, causes impaired autophagy, but it has remained unclear how this predisposes to CD.

Model: Mice that lack Atg16l1 in intestinal epithelial cells (IECs) (Atg16l1ΔIEC) phenocopying ileal CD observed in humans homozygous for ATG16L1T300A.

Aim: Investigation of the mechanisms engaged by impaired ATG16L1-dependent autophagy that drive ileal inflammation.

Results: Defective autophagy in IECs predispose to CD ileitis via impaired clearance of endoplasmic reticulum (ER) stress sensor IRE1α aggregates during ER stress.
IRE1α accumulates in Paneth cells, specialized IECs, of Atg16l1ΔIEC mice, and humans homozygous for ATG16L1T300A exhibit a corresponding increase of IRE1α in intestinal epithelial crypts.

Figure 1. 35-week-old Atg16l1ΔIEC mice exhibit increased ER stress and transmural CD-like ileitis.

Figure 1 - Atg16l1ΔIEC mice

A-B) Representative H&E images (B) and enteritis histology score (C) of 35-week-old Atg16l1ΔIEC mice.

Figure 2. IRE1α expression is increased in 35-week-old Atg16l1ΔIEC mice and ATG16L1T300A patients and drives CD-like ileitis.

Figure 2a - Atg16l1ΔIEC mice

A) Representative confocal images of IRE1α immunoreactivity (green; white arrows) in 10- and 35-week-old Atg16l1ΔIEC mice.

Figure 2b - Atg16l1ΔIEC mice

B) Representative IRE1α immunoreactivity (green) stratified by the ATG16L1 risk allele (AA/AG/GG; A, healthy allele; G risk allele) in healthy controls (n = 9/22/12) and noninflamed mucosa (n = 9/15/7) of CD patients.

C) Quantification of IRE1α+ crypts shown in B in healthy controls (n = 9/22/12) and CD patients (n = 9/15/7) according to their ATG16L1 genotype (n = 18/37/19).

Validation

Related resources and publications
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