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Diploid embryo complementation of embryonic stem cells efficiently generates a homozygous Gjb2 mutant deaf mouse model

ABSTRACT: Our work demonstrates that generating all ESC-derived mice via diploid embryo complementation is more efficient and feasible than the tetraploid approach. The broad application of this method will significantly accelerate the construction of disease models and xenogeneic chimeras using stem cell technology. Besides, our results indicate that the cell fate plasticity of eight-cell embryos is both flexible and variable. This plasticity is influenced by material exchange, through which embryonic stem cells transmit information, similar to the transmission of information from the second polar body. The efficient generation of Gjb235delG/35delG mice via diploid complementation will accelerate the understanding of pathogenic mechanisms and the investigation of therapeutic effects for hereditary deafness. Additionally, other disease models with GJB2 pathogenic mutations (235delC, V27I, R75W, etc.) can also be efficiently produced using this method for pre-clinical research

ORGANISM(S): Mus musculus

PROVIDER: GSE271800 | GEO | 2026/07/01

REPOSITORIES: GEO

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The pathogenesis of common Gjb2 mutation associated with human hereditary deafness in mice

Project description:Mutations in GJB2 (Gap junction protein beta 2) are the most common genetic cause of non-syndromic hereditary deafness in humans, especially the 35delG and 235delC mutations. Owing to the homozygous-lethal of Gjb2 mutation in mice, there are currently no perfect mouse models carrying Gjb2 mutation to mimic human hereditary deafness and unveil the pathogenesis. Here, we first constructed heterozygous mutant mice, Gjb2+/35delG and Gjb2+/235delC, through androgenic haploid embryonic stem cells (AG-haESCs) mediated semi-cloning technology, which showed normal hearing function at P28. Furthermore, a homozygous mutant mouse model, Gjb235delG/35delG, was generated via enhanced tetraploid embryo complementation, which exhibited profound hearing loss like human patients at P14. Mechanism analysis showed that Gjb2 35delG disrupts the formation of intercellular gap junction channel and tunnel of Corti, and hair cell mechanotransduction, rather than the development of hair cells. Collectively, our study provides ideal mouse models for understanding the pathogenic mechanism and opens up a new avenue for investigating the treatment for DFNB1A-related hereditary deafness.

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