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

Authors

  • Kamila U. Szulc,

    1. Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York, USA
    2. Biomedical Imaging Program, New York University School of Medicine, New York, New York, USA
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  • Brian J. Nieman,

    1. Mouse Imaging Centre, Hospital for Sick Children, Toronto, Ontario, Canada
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  • Edward J. Houston,

    1. Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York, USA
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  • Benjamin B. Bartelle,

    1. Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York, USA
    2. Molecular Biophysics Graduate Program, New York University School of Medicine, New York, New York, USA
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  • Jason P. Lerch,

    1. Mouse Imaging Centre, Hospital for Sick Children, Toronto, Ontario, Canada
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  • Alexandra L. Joyner,

    1. Developmental Biology Program, Sloan-Kettering Institute, New York, New York, USA
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  • Daniel H. Turnbull

    Corresponding author
    1. Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York, USA
    2. Biomedical Imaging Program, New York University School of Medicine, New York, New York, USA
    3. Molecular Biophysics Graduate Program, New York University School of Medicine, New York, New York, USA
    4. Department of Radiology, New York University School of Medicine, New York, New York, USA
    5. Department of Pathology, New York University School of Medicine, New York, New York, USA
    • Correspondence to: Daniel H. Turnbull, Ph.D., Skirball Institute of Biomolecular Medicine, New York University School of Medicine, 540 First Avenue, New York, NY 10016. E-mail: daniel.turnbull@med.nyu.edu

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Abstract

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.

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