Generating mouse models for biomedical research: technological advances.

Channabasavaiah B Gurumurthy,Kevin C Kent Lloyd

doi:10.1242/dmm.029462

Abstract

ABSTRACTOver the past decade, new methods and procedures have been developed to generate genetically engineered mouse models of human disease. This At a Glance article highlights several recent technical advances in mouse genome manipulation that have transformed our ability to manipulate and study gene expression in the mouse. We discuss how conventional gene targeting by homologous recombination in embryonic stem cells has given way to more refined methods that enable allele-specific manipulation in zygotes. We also highlight advances in the use of programmable endonucleases that have greatly increased the feasibility and ease of editing the mouse genome. Together, these and other technologies provide researchers with the molecular tools to functionally annotate the mouse genome with greater fidelity and specificity, as well as to generate new mouse models using faster, simpler and less costly techniques.

Highlights

Researchers are entering a new era of human disease modeling in animals
Even mouse models that only partially recapitulate the human phenotype, such as mutations in individual paralogs, can still provide important insights into disease mechanisms. In this At a Glance article, we review recent technological advances for generating new and improved mouse models for biomedical research
We focus on the generation of more-complex alleles in embryonic stem (ES) cells (Poster panel 1) that retain wild-type expression and are amenable to conditional, tissuespecific and/or time-dependent deletion

Summary

Introduction

Researchers are entering a new era of human disease modeling in animals. For many years the laboratory mouse (Mus musculus) has remained the quintessential research animal of choice for studying human biology, pathology and disease processes (Rosenthal and Brown, 2007; Lloyd et al, 2016). It is important to note that, as technologies for genetic engineering and phenotypic analysis have advanced, some studies using mouse models have struggled to accurately predict human disease pathogenesis and clinical response to drug therapy (Perrin, 2014). For these reasons, it is essential to apply scientific principles of rigor and reproducibility (Kilkenny et al, 2010; Karp et al, 2015) when designing and conducting experiments to associate mouse genes with human phenotypes at a systems level (Perlman, 2016)

Objectives

Findings

Conclusion