Anatomical phenotyping in the brain and skull of a mutant mouse by magnetic resonance imaging and computed tomography

Abstract

Since genetically modified mice have become more common in biomedical research as models of human disease, a need has also grown for efficient and quantitative methods to assess mouse phenotype. One powerful means of phenotyping is characterization of anatomy in mutant vs. normal populations. Anatomical phenotyping requires visualization of structures in situ, quantification of complex shape differences between mouse populations, and detection of subtle or diffuse abnormalities during high-throughput survey work. These aims can be achieved with imaging techniques adapted from clinical radiology, such as magnetic resonance imaging and computed tomography. These imaging technologies provide an excellent nondestructive method for visualization of anatomy in live individuals or specimens. The computer-based analysis of these images then allows thorough anatomical characterizations. We present an automated method for analyzing multipleimage data sets. This method uses image registration to identify corresponding anatomy between control and mutant groups. Withinand between-group shape differences are used to map regions of significantly differing anatomy. These regions are highlighted and represented quantitatively by displacements and volume changes. This methodology is demonstrated for a partially characterized mouse mutation generated by N-ethyl-N-nitrosourea mutagenesis that is a putative model of the human syndrome oculodentodigital dysplasia, caused by point mutations in the gene encoding connexin 43. image processing; GJA1; connexin 43; oculodentodigital dysplasia.

Distinct cerebellar foliation anomalies in a CHD7 haploinsufficient mouse model of CHARGE syndrome

“…At completion of this registration, all scans had been deformed into alignment with each other in an unbiased fashion. As with typical deformation based morphometry, this allows for analysis of the deformations required to register the anatomy of each individual mouse into the final atlas space (Lerch et al, 2008; Nieman, Flenniken, Adamson, Henkelman, & Sled, 2006). The Jacobian determinants, as calculated through this analysis process, were used as measures of volume at each voxel and compared across genotypes.…”

Shape Modeling and Analysis with Entropy-Based Particle Systems

“…Additionally, computational models have the advantage that they are volumetric, noninvasive, and more easily adapted to high-throughput phenotypic screening. Several researchers have proposed computational shape models for mouse brain phenotype using deformable registration between groups of mean MRI images [83] and deformable registration to a normal atlas [19]. To date, however, there has been little work done to investigate the use of correspondence models for genetic phenotyping, which is a focus of this dissertation.…”

Mouse behavioral mutants have neuroimaging abnormalities

“…In a similar fashion to population-based neuroimaging studies in humans, comparisons of genetically-modified mouse images with appropriate control images permits characterization of anatomical and morphological differences, which can subsequently be attributed to genetic factors. Although some phenotypes are evident by simple visual inspection, more detailed, quantitative comparisons can be computerautomated for detection of local changes in shape and size through image registration [Collins and Evans, 1997;Woods et al, 1998aWoods et al, , 1998b and analysis of the resultant deformation fields [Cao and Worsley, 1999;Chen et al, 2006;Kovacevic et al, 2005;Nieman et al, 2006;Thompson et al, 1997]. In inbred mice, where genetic variability is tightly controlled, a relatively small number of subjects are expected to be representative of the population, thus these analyses are possible with fewer individuals.…”