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Clarifying Frizzled 2 function in development through genetically validated mouse models
Megan N Michalski1, Cassandra R Diegel1, Zhendong A Zhong1
1Department of Cell Biology, Van Andel Institute, Grand Rapids, Michigan 49503, USA.
Abstract:
Wnt receptors of the Frizzled (Fzd) family are widely considered to exhibit substantial functional redundancy, complicating efforts to therapeutically target individual receptors. Fzd2 was believed to be functionally redundant with Fzd1 and Fzd7, based on previously published global knockout mouse studies. By contrast, homozygosity for a Fzd2 global knockout mouse allele developed by the International Mouse Phenotype Consortium (IMPC) has been reported to cause embryonic lethality, suggesting that Fzd2 is critical for early embryonic development. If global deletion of Fzd2 leads to early lethality, conditional deletion models are necessary to identify tissue-specific phenotypes. We found that a previously published Fzd2 conditional deletion model does not eliminate Fzd2. We have generated a new conditional model to address the contradictory previous studies and allow tissue-specific studies of Fzd2. We successfully inserted two loxP sites around the Fzd2 gene and confirmed that subsequent Cre-mediated recombination creates a Fzd2 null allele. Global deletion of Fzd2 in this model does not cause embryonic lethality while limb-specific deletion causes limb shortening. This work supports the hypothesis that Fzd2 regulates limb development and emphasizes the importance of thoroughly validating newly generated mouse models.
Insights
Frizzled-2 (Fzd2) is crucial for limb development, not just redundant. A new mouse model shows Fzd2 knockout causes limb shortening, clarifying its essential role in embryonic development.
Area of Science:
- Developmental Biology
- Genetics
- Molecular Biology
Background:
- Frizzled (Fzd) receptors, particularly Fzd2, are thought to have functional redundancy.
- Previous studies on Fzd2 global knockout mice yielded conflicting results regarding embryonic lethality and Fzd2's specific role.
- Existing conditional Fzd2 knockout models were found to be ineffective in fully eliminating Fzd2 expression.
Purpose of the Study:
- To generate and validate a new conditional mouse model for Fzd2.
- To investigate the specific role of Fzd2 in embryonic development, particularly in limb formation.
- To resolve discrepancies in previous Fzd2 knockout studies.
Main Methods:
- Generation of a novel conditional Fzd2 knockout mouse model by flanking the Fzd2 gene with loxP sites.
- Confirmation of Cre-mediated recombination leading to a Fzd2 null allele.
- Analysis of phenotypes resulting from global and limb-specific Fzd2 deletion.
Main Results:
- Global deletion of Fzd2 in the new model did not result in embryonic lethality.
- Limb-specific deletion of Fzd2 led to significant limb shortening.
- The new conditional model effectively allows for tissue-specific Fzd2 ablation.
Conclusions:
- Fzd2 plays a critical, non-redundant role in mammalian limb development.
- The validated conditional model is essential for future tissue-specific Fzd2 research.
- Thorough validation of mouse models is crucial for accurate scientific findings.
