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A Mouse Model for the Rapid and Binomial Assessment of Putative WNT/β-Catenin Signalling Inhibitors

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posted on 2023-11-14, 03:42 authored by Janson Tse, Ryan O'KeefeRyan O'Keefe, Angela Rigopolous, Annalisa Leandra Elena CarliAnnalisa Leandra Elena Carli, Jo Waaler, Stefan Krauss, Matthias ErnstMatthias Ernst, Michael BuchertMichael Buchert
Specific signalling thresholds of the WNT/β-catenin pathway affect embryogenesis and tissue homeostasis in the adult, with mutations in this pathway frequently occurring in cancer. Excessive WNT/β-catenin activity inhibits murine anterior development associated with embryonic lethality and accounts for the driver event in 80% of human colorectal cancers. Uncontrolled WNT/β-catenin signalling arises primarily from impairment mutation in the tumour suppressor gene APC that otherwise prevents prolonged stabilisation of β-catenin. Surprisingly, no inhibitor compounds for WNT/β-catenin signalling have reached clinical use in part owing to the lack of specific in vivo assays that discriminate between on-target activities and dose-limiting toxicities. Here, we present a simple in vivo assay with a binary outcome whereby the administration of candidate compounds to pregnant and phenotypically normal Apcflox/flox mice can rescue in utero death of Apcmin/flox mutant conceptus without subsequent post-mortem assessment of WNT/β-catenin signalling. Indeed, the phenotypic plasticity of born Apcmin/flox conceptus enables future refinement of our assay to potentially enable dosage finding and cross-compound comparisons. Thus, we show for the first time the suitability of endogenous WNT/β-catenin signalling during embryonic development to provide an unambiguous and sensitive mammalian in vivo model to assess the efficacy and bioavailability of potential WNT/β-catenin antagonists.


This research was funded by the National Health and Medical Research Council of Australia (NHMRC) Senior Research Fellowship (1079257 to M.E.), Program Grant (1092788 to M.E.) and Investigator Grant (1173814 to M.E.), an NHMRC Project Grant (1143020 to M.B.), the NHMRC Ideas Grant (2020316 to M.B.) and a La Trobe RFA Understanding Disease grant to M.B., and the Operational Infrastructure Support Program, Victorian Government, Australia. J.W. was supported by grants from the South-Eastern Norway Regional Health Authority (2019090 and 2021035), and S.K. was supported by the Research Council of Norway (174938/O30).


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© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (