An impending crisis in the provision of histopathology expertise for mouse functional genomics.

The generation of new mouse models of human disease is accelerating rapidly, due to the completion of whole-genome sequencing efforts and technological advances in the manipulation of the mouse genome. We sought to investigate manpower issues in the provision of histopathology expertise for mouse functional genomics and compared this to the perceived demand from principal investigators (PIs). Through the European Commission (EC)-funded PRIME pathology training initiative, two questionnaires were devised to collect information from pathologists and EC-funded PIs on the current provision of mouse histopathology expertise in Europe and the demands for this service. We find that pathological analysis is being performed almost exclusively by professionally qualified pathologists, generally employed in clinical diagnostic posts, where the work is undertaken as collaboration outside of their contractual commitments but without previous training in veterinary or comparative pathology. The results indicate that there is a lack of both trainees and provision of specialist training in this field. Unsurprisingly, the availability of diagnostic expertise and advice falls far short of the number of genetically engineered mice (GEM) being generated for analysis. We analyse these results with reference to previous studies and discuss solutions for the future recruitment, training and funding for pathologists in mouse functional genomics in Europe.

Analysis of breeding and pathology helps refine management practices of a large-scale N'-ethyl-N'-nitrosourea mouse mutagenesis programme.

N'-ethyl-N'-nitrosourea (ENU) is a powerful germline mutagen used in conjunction with phenotype-driven screens to generate novel mouse mutants. ENU also induces genetic lesions in somatic cells and dosage requires optimization between maximum germline mutation rate versus induced sterility and tumourigenesis that compromise the welfare and fecundity of the ENU-treated males. Here, we present our experience with BALB/cAnNCrl and C57BL/6J mice in terms of the pathology induced by ENU and its impact on breeding. In both mouse strains, morbidity and mortality rises with ENU dose. In more than 75% of C57BL/6J males, morbidity and mortality were attributable to the development of malignant T-lymphoblastic lymphoma. Approximately 50% of ENU-treated BALB/cAnNCrl males develop early malignant T-lymphoblastic lymphoma, but the cohort that survives develops late-onset lung carcinoma. Within strains, the latency of these clinically important tumour(s) was not dosage-dependent, but the proportion of mice developing tumours and consequently removed from the breeding programme increased with ENU dosage. The median number of offspring per ENU-treated C57BL/6J male in standard matings with C3H/HeH females decreased with increasing dosage. The two most important underlying causes for lower male fecundity were increased infertility in the highest dosage group and reduced numbers of litters born to the remaining fertile C57BL/6J males due to a higher incidence of morbidity. These findings have allowed us to refine breeding strategy. To maximize the number of offspring from each ENU-treated male, we now rotate productive males between two cages to expose them to more females. This optimizes the number of mutation carrying offspring while reducing the number of ENU-treated males that must be generated.