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?-CateninC429S mice exhibit sterility consequent to spatiotemporally sustained Wnt signalling in the internal genitalia.

ABSTRACT: Wnt/?-catenin signalling regulates numerous developmental and homeostatic processes. Ctnnb1 (also known as ?-catenin) is the only protein that transmits signals from various Wnt ligands to downstream genes. In this study, we report that our newly established mouse strain, which harbours a Cys429 to Ser missense mutation in the ?-catenin gene, exhibited specific organ defects in contrast to mice with broadly functioning Wnt/?-catenin signalling. Both homozygous mutant males and females produced normal gametes but were infertile because of abnormal seminal vesicle and vaginal morphogenesis. An ins-TOPGAL transgenic reporter spatiotemporally sustained Wnt/?-catenin signalling during the corresponding organogenesis. Therefore, ?-catenin(C429S) should provide new insights into ?-catenin as a universal component of Wnt/?-catenin signal transduction.

SUBMITTER: Murata T

PROVIDER: S-EPMC4223658 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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β-CateninC429S mice exhibit sterility consequent to spatiotemporally sustained Wnt signalling in the internal genitalia.

Murata Takuya T Ishitsuka Yuichi Y Karouji Kumiko K Kaneda Hideki H Toki Hideaki H Nakai Yuji Y Makino Shigeru S Fukumura Ryutaro R Kotaki Hayato H Wakana Shigeharu S Noda Tetsuo T Gondo Yoichi Y

Scientific reports 20141107

Wnt/β-catenin signalling regulates numerous developmental and homeostatic processes. Ctnnb1 (also known as β-catenin) is the only protein that transmits signals from various Wnt ligands to downstream genes. In this study, we report that our newly established mouse strain, which harbours a Cys429 to Ser missense mutation in the β-catenin gene, exhibited specific organ defects in contrast to mice with broadly functioning Wnt/β-catenin signalling. Both homozygous mutant males and females produced n ...[more]

PMID: 25376241

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Project description:Wnt proteins modulate cell proliferation and differentiation and the self-renewal of stem cells by inducing ?-catenin-dependent signalling through the Wnt receptor frizzled (FZD) and the co-receptors LRP5 and LRP6 to regulate cell fate decisions and the growth and repair of several tissues. The 19 mammalian Wnt proteins are cross-reactive with the 10 FZD receptors, and this has complicated the attribution of distinct biological functions to specific FZD and Wnt subtype interactions. Furthermore, Wnt proteins are modified post-translationally by palmitoylation, which is essential for their secretion, function and interaction with FZD receptors. As a result of their acylation, Wnt proteins are very hydrophobic and require detergents for purification, which presents major obstacles to the preparation and application of recombinant Wnt proteins. This hydrophobicity has hindered the determination of the molecular mechanisms of Wnt signalling activation and the functional importance of FZD subtypes, and the use of Wnt proteins as therapeutic agents. Here we develop surrogate Wnt agonists, water-soluble FZD-LRP5/LRP6 heterodimerizers, with FZD5/FZD8-specific and broadly FZD-reactive binding domains. Similar to WNT3A, these Wnt agonists elicit a characteristic ?-catenin signalling response in a FZD-selective fashion, enhance the osteogenic lineage commitment of primary mouse and human mesenchymal stem cells, and support the growth of a broad range of primary human organoid cultures. In addition, the surrogates can be systemically expressed and exhibit Wnt activity in vivo in the mouse liver, regulating metabolic liver zonation and promoting hepatocyte proliferation, resulting in hepatomegaly. These surrogates demonstrate that canonical Wnt signalling can be activated by bi-specific ligands that induce receptor heterodimerization. Furthermore, these easily produced, non-lipidated Wnt surrogate agonists facilitate functional studies of Wnt signalling and the exploration of Wnt agonists for translational applications in regenerative medicine.

Dataset Information

?-CateninC429S mice exhibit sterility consequent to spatiotemporally sustained Wnt signalling in the internal genitalia.

Publications

β-CateninC429S mice exhibit sterility consequent to spatiotemporally sustained Wnt signalling in the internal genitalia.

Similar Datasets

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