A time-dependent conditional Knockout mouse defines an inducible animal model in which a gene of interest is "floxed" thus temporally controllable at a given time-point in embryonic, post-natal or adult animals.

After an additional breeding step with a Cre-ERt2 deleter mouse line, the conditional Knockout is temporally triggered by external inducer-agents, most often small molecules such as tamoxifen or tetracycline.


For academic research:

  • Comparative study of gene function (on- vs. offset)
  • Mimic a pathology with late onset
  • Studying embryonic lethal conditions

For bio-pharmaceutical research & development:

  • Target validation studies
  • Off-target effects studies
  • Mimicking 100% antagonism
  • Compensatory phenotype rescue (compounds testing)

Strengths of time-dependent Knockout mouse models

  • Very flexible: easy switch to study time-dependent KOs in different tissues
  • Large resource of deleter mice (Cre or FLP) enabling an almost infinite combination of time-dependent KOs in different tissues
  • High physiological relevancy of the scientific data obtained from the model
  • Many deletion-inducible lines (thousands of Cre-FLP mouse lines...) enabling almost infinite specificity

Limitations of time-dependent Knockout mouse models

  • Expression levels dependent on the dose of the agent administered
  • Differential penetration of trigger compound into tissue
  • Availability and background of Cre inducer lines
  • Adding the loxP sites risks modification or disruption of splicing regulation (ESS ESE); possible impact on overlapping and neighboring genes
    → Need careful analysis of the placement of loxP sites
  • Tetracycline-inducible systems can be leaky
    → Temporal control can be achieved by using a fusion between Cre and a mutated form of the ligand-binding domain of the estrogen receptor which only binds tamoxifen (ERt and ERt2). This inactive Cre-ERt2 fusion is activated upon tamoxifen (or 4-hydroxytamoxifen) administration.

Case study

Model to circumvent embryonic lethality and study male germ cells

Nilsen A, et al. ALKBH4 depletion in mice leads to spermatogenic defects. PLoS One. 2014.

ALKBH4 indirectly influences the ability of non-muscular myosin II to bind actin filaments. It modulates fundamental processes including cytokinesis and cell motility, and its depletion is lethal during early preimplantation embryo stage.

Model: Conditional Alkbh4L/L (flanked by loxP) mice crossed with CreEsr transgenic mice to create the inducible Knockout genotype Alkbh4L/L CreEsr overcoming the embryonic lethality.

Aim: Investigate the effect of ALKBH4 deficiency in a physiological context, using inducible Alkbh4 Knockout mice.

Results: ALKBH4 is essential for the development of spermatocytes during the prophase of meiosis.

Figure 1. Tamoxifen (TAM) treatment and suppression of Alkbh4.

Figure 1a - Alkbh4L/L mice

A) Schematic outline of TAM treatment in of Alkbh4L/L CreEsr and control mice day 0 to 14 with indicated time-­points for sampling.

B) Cre-­mediated recombination of the loxP-­flanked DNA sequence in selected organs of Alkbh4 mice after 2 weeks of tamoxifen treatment detected by PCR.

Figure 1b - Alkbh4L/L mice

C) Depletion of ALKBH4 in whole-­testis extracts of Alkbh4Δ/Δmice after 2 weeks of tamoxifen treatment detected by Western blot.

Figure 1c - Alkbh4L/L mice

Figure 2. Loss of Alkbh4 reduces the size of testis

Figure 2 - Alkbh4L/L mice

Left panel) Representative testes from control and Alkbh4 mice after tamoxifen treatment for one week or without treatment (0-1 week), and after deletion of Alkbh4 with treatment for 2 weeks.

Right panel) Average testis/body weight ratio of 4-5-week-old mice before and after 1 week of treatment with tamoxifen (0-1 week), and 6-week-old mice treated with tamoxifen for 2 weeks (0-1 week).

Figure 3. Stage­-specific arrest of spermatogenesis in Alkbh4Δ/Δ mice.

A) Immunofluorescence labeling of histological sections for anti-γH2A.X (red) with DAPI (blue) counterstain, where Sertoli cells (Se), leptotene (L) and pachytene (P) spermatocytes and elongating spermatids (S9) can be distinguished.

Figure 3a - Alkbh4L/L mice

B) Mean cell density per cross­-section of stage IX (n>10 tubuli per histological section, total of 6 sections) from control (Alkbh4L/L) and Alkbh4Δ/Δ mice treated with tamoxifen for 1-2 weeks shows severe depletion of pachytene spermatocytes and S9 elongating spermatids after 2 weeks of tamoxifen treatment in Alkbh4Δ/Δ mice.

Figure 3b - Alkbh4L/L mice

C) Mean cell density at selected stages (I, VIII, IX) of spermatogenesis in Alkbh4Δ/Δ mice indicates depletion of cells at pachynema and all subsequent stages.

Figure 3c - Alkbh4L/L mice
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