Novel skin phenotypes revealed by a genome-wide mouse reverse genetic screen.

Kifayathullah Liakath-Ali,Emma Heath,Valerie E Vancollie,Ramiro Ramirez-Solis,Ian Smyth,Tia Ditommaso,Damian P Smedley,Karen P Steel,Jacqueline K White,Fiona M Watt,David Sunter,Jeanne Estabel

doi:10.1038/ncomms4540

Abstract

Permanent stop-and-shop large-scale mouse mutant resources provide an excellent platform to decipher tissue phenogenomics. Here we analyse skin from 538 knockout mouse mutants generated by the Sanger Institute Mouse Genetics Project. We optimize immunolabelling of tail epidermal wholemounts to allow systematic annotation of hair follicle, sebaceous gland and interfollicular epidermal abnormalities using ontology terms from the Mammalian Phenotype Ontology. Of the 50 mutants with an epidermal phenotype, 9 map to human genetic conditions with skin abnormalities. Some mutant genes are expressed in the skin, whereas others are not, indicating systemic effects. One phenotype is affected by diet and several are incompletely penetrant. In-depth analysis of three mutants, Krt76, Myo5a (a model of human Griscelli syndrome) and Mysm1, provides validation of the screen. Our study is the first large-scale genome-wide tissue phenotype screen from the International Knockout Mouse Consortium and provides an open access resource for the scientific community.

Highlights

Permanent stop-and-shop large-scale mouse mutant resources provide an excellent platform to decipher tissue phenogenomics
Discussion that large numbers of mouse mutants are available through the International Knockout Mouse Consortium[45], there is a need to screen phenotypes via correspondingly high-throughput approaches
By making phenotype data available immediately via an open access resource, results can be rapidly and widely disseminated, and potential interactions between genes or between phenotypes can be revealed. We have used this approach to carry out the first large-scale tissue-specific screen of mutants from the Mouse Genetics Project (MGP)

Summary

Introduction

Permanent stop-and-shop large-scale mouse mutant resources provide an excellent platform to decipher tissue phenogenomics. Our study is the first large-scale genome-wide tissue phenotype screen from the International Knockout Mouse Consortium and provides an open access resource for the scientific community. A large-scale highthroughput systematic functional screen for genes involved in skin homeostasis was not feasible until recently. Genome-wide approaches to epidermal function include short interfering RNA-based genetic screens in cultured human epidermal cells[8] and RNA interference-mediated gene knockdown via in utero microinjection of lentiviral vectors[9]. A further challenge is that it is extremely laborious to assess phenotypes in large areas of adult skin by relying on conventional histological sections This can be overcome by preparing wholemounts of intact tail epidermis[10] in which the interfollicular epidermis (IFE), sebaceous glands (SGs) and hair follicles (HFs) are discerned. Identifying the phenotype correlations of genes involved in skin homeostasis paves the way to interrogate functional genetic interactions and find therapeutic targets for human skin diseases

Methods

Results

Conclusion