Similarly,

analysis of numbers that would be unfeasible by conventional histology allows phenotypes that show variable or low penetrance to be investigated. It has, for example, been possible using HREM to investigate the precise range and type of cardiac malformations occurring in embryos of a trans-chromosomic mouse which incorporates ALK inhibitor the majority of human chromosome 21 as well as the normal diploid mouse genome. As a mouse model for studying human Down syndrome (DS), studies of this line are potentially compromised by low penetrance of the phenotype which may result from both tissue variability and mosaic retention of the human chromosome. Nevertheless,

through studying sufficient numbers by HREM it has been possible to identify most of LBH589 cell line the same cardiac malformations seen in DS individuals, including the hallmark atrioventricular septal defect, albeit at relatively low prevalence [27•]. The same study used the high throughput possible with HREM to identify a significant difference in frequency of malformation between different mouse strain backgrounds. Anecdotally, the contributory effect of strain background on phenotype is well known amongst researchers and has been noted in many studies, including those characterising cardiac phenotypes. Although it is both costly and difficult to characterise systematically, this may prove important for developing the accurate experimental models of human cardiac malformation or disease. Indeed, whilst differences between strains are known to affect animal husbandry, whether they have significant impact on aspects of normal development remains largely unexplored. Our own studies Thiamine-diphosphate kinase using HREM indicate that background strain and the degree of outbreeding

can affect not only subtle effects on the relative timing of developmental changes during embryogenesis, but can also have profound qualitative and quantitative effects on aspects of cardiac morphology such as patterning or position of the coronary arteries and dimensions of the pharyngeal arch arteries [28]. The detail provided by HREM images combined with the ability to manipulate entire data sets in 3D not only enables cardiac and vascular morphology to be visualised. It also allows accurate measurement of individual structures. To date, most analysis of heart development in the mouse has focussed on qualitative comparisons of normal and mutant hearts, usually using selected 2D histological sections. Quantitative measurements from such data are of course possible using techniques of unbiased stereology, but only if appropriately extensive and comparable section series are available.