MRI analysis of cerebellar and vestibular developmental phenotypes in Gbx2 conditional knockout mice

• Published in: Magnetic resonance in medicine Vol. 70; no. 6; pp. 1707 - 1717
• Main Authors: Szulc, Kamila U., Nieman, Brian J., Houston, Edward J., Bartelle, Benjamin B., Lerch, Jason P., Joyner, Alexandra L., Turnbull, Daniel H.
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01-12-2013; Wiley Subscription Services, Inc
• Subjects: Animal models; Animals; Animals, Newborn; brain development; cerebellum; Cerebellum - abnormalities; Cerebellum - growth & development; Cerebellum - pathology; Cerebellum - physiopathology; Developmental Disabilities - genetics; Developmental Disabilities - pathology; Developmental Disabilities - physiopathology; gastrulation brain homeobox 2 gene (Gbx2); Homeodomain Proteins - genetics; Magnetic Resonance Imaging - methods; manganese-enhanced MRI (MEMRI); Mice; Mice, Knockout; mid-hindbrain; Nervous System Malformations - genetics; Nervous System Malformations - pathology; Nervous System Malformations - physiopathology; Phenotype; Reproducibility of Results; Sensitivity and Specificity; Vestibule, Labyrinth - abnormalities; Vestibule, Labyrinth - growth & development; Vestibule, Labyrinth - pathology; vestibulo-cochlear organ; brain development; mid-hindbrain; manganese-enhanced MRI (MEMRI); cerebellum; gastrulation brain homeobox 2 gene (Gbx2); vestibulo-cochlear organ
• ISSN: 0740-3194; 1522-2594
• DOI: 10.1002/mrm.24597

Purpose
Our aim in this study was to apply three‐dimensional MRI methods to analyze early postnatal morphological phenotypes in a Gbx2 conditional knockout (Gbx2‐CKO) mouse that has variable midline deletions in the central cerebellum, reminiscent of many human cerebellar hypoplasia syndromes.
Methods
In vivo three‐dimensional manganese‐enhanced MRI at 100‐µm isotropic resolution was used to visualize mouse brains between postnatal days 3 and 11, when cerebellum morphology undergoes dramatic changes. Deformation‐based morphometry and volumetric analysis of manganese‐enhanced MRI images were used to, respectively, detect and quantify morphological phenotypes in Gbx2‐CKO mice. Ex vivo micro‐MRI was performed after perfusion‐fixation with supplemented gadolinium for higher resolution (50‐µm) analysis.
Results
In vivo manganese‐enhanced MRI and deformation‐based morphometry correctly identified known cerebellar defects in Gbx2‐CKO mice, and novel phenotypes were discovered in the deep cerebellar nuclei and the vestibulo‐cerebellum, both validated using histology. Ex vivo micro‐MRI revealed subtle phenotypes in both the vestibulo‐cerebellum and the vestibulo‐cochlear organ, providing an interesting example of complementary phenotypes in a sensory organ and its associated brain region.
Conclusion
These results show the potential of three‐dimensional MRI for detecting and analyzing developmental defects in mouse models of neurodevelopmental diseases. Magn Reson Med 70:1707–1717, 2013. © 2013 Wiley Periodicals, Inc.