A Mary Lyon Centre GEMM Mouse Model Supports Male Fertility Research

A conditional mouse model generated by the Mary Lyon Centre’s Genome Editing Mice for Medicine (GEMM) programme is being used by researchers at Newcastle University to investigate the role of an ultra-conserved exon in the splicing regulator gene Tra2b.

Many genes function as instructions for producing proteins, which perform the majority of tasks within our cells. To enable greater complexity without increasing the number of genes needed, multiple versions of a protein can be made from a single gene, via a process called splicing. This involves modules within a gene being included or excluded from the final protein product. In some cases, a module, called a poison exon, can be included to introduce an early “stop” instruction, which prevents a functional protein being made.

The gene Tra2b encodes a splicing regulator that promotes inclusion of its own poison exon, as well as affecting the splicing of other genes. This creates a feedback loop in which increased levels of the functional Tra2β protein block further protein production. Interestingly, the Tra2b poison exon is defined as being ultra-conserved, as it shows 100% sequence identity between human, mouse, and rat, while also retaining 96% identity across 300 million years of evolution between human, chicken, and lizard! This not only suggests that the mouse can provide a useful model for studying the function of this poison exon but also underscores its likely biological importance.

To support his group’s investigation of the role of this poison exon, David Elliott, Professor of Genetics at Newcastle University, applied to the Mary Lyon Centre’s second GEMM call in 2017 to have a mouse generated with the Tra2b poison exon flanked by LoxP sites, using CRISPR/Cas9. This creates a mouse line that, when crossed with different Cre-expressing mice, allows the removal of the poison exon with precise spatial and/or temporal control.

Read more at Mary Lyon Centre website.