Magnetic resonance virtual histology for embryos: 3D atlases for automated high-throughput phenotyping.
Ambitious international efforts are underway to produce gene-knockout mice for each of the 25,000 mouse genes, providing a new platform to study mammalian development and disease. Robust, large-scale methods for morphological assessment of prenatal mice will be essential to this work. Embryo phenotyping currently relies on histological techniques but these are not well suited to large volume screening. The qualitative nature of these approaches also limits the potential for detailed group analysis. Advances in non-invasive imaging techniques such as magnetic resonance imaging (MRI) may surmount these barriers. We present a high-throughput approach to generate detailed virtual histology of the whole embryo, combined with the novel use of a whole-embryo atlas for automated phenotypic assessment. Using individual 3D embryo MRI histology, we identified new pituitary phenotypes in Hesx1 mutant mice. Subsequently, we used advanced computational techniques to produce a whole-body embryo atlas from 6 CD-1 embryos, creating an average image with greatly enhanced anatomical detail, particularly in CNS structures. This methodology enabled unsupervised assessment of morphological differences between CD-1 embryos and Chd7 knockout mice (n=5 Chd7(+/+) and n=8 Chd7(+/-), C57BL/6 background). Using a new atlas generated from these three groups, quantitative organ volumes were automatically measured. We demonstrated a difference in mean brain volumes between Chd7(+/+) and Chd7(+/-) mice (42.0 vs. 39.1mm(3), p<0.05). Differences in whole-body, olfactory and normalised pituitary gland volumes were also found between CD-1 and Chd7(+/+) mice (C57BL/6 background). Our work demonstrates the feasibility of combining high-throughput embryo MRI with automated analysis techniques to distinguish novel mouse phenotypes.
Cleary
Jon O
JO
Centre for Advanced Biomedical Imaging, Department of Medicine, University College London, London, UK.
Modat
Marc
M
Norris
Francesca C
FC
Price
Anthony N
AN
Jayakody
Sujatha A
SA
Martinez-Barbera
Juan Pedro
JP
Greene
Nicholas D E
ND
Hawkes
David J
DJ
Ordidge
Roger J
RJ
Scambler
Peter J
PJ
Ourselin
Sebastien
S
Lythgoe
Mark F
MF
D000818:Animals; D001271:Atlases as Topic; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D004622:Embryo, Mammalian / Q000033:anatomy & histology*; D057166:High-Throughput Screening Assays / Q000379:methods*; D006652:Histological Techniques; D021621:Imaging, Three-Dimensional / Q000379:methods*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D014584:User-Computer Interface
C507367:Chd7 protein, mouse; D004268:DNA-Binding Proteins