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Published on: May 12, 2015
Mbnl1 and Mbnl2 regulate brain structural integrity in mice
Naomi S Sta Maria1, Chenyu Zhou2, Se Jung Lee2
1Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Abstract:
Myotonic Dystrophy Type I (DM1) patients demonstrate widespread and variable brain structural alterations whose etiology is unclear. We demonstrate that inactivation of the Muscleblind-like proteins, Mbnl1 and Mbnl2, initiates brain structural defects. 2D FSE T2w MRIs on 4-month-old Mbnl1+/-/Mbnl2-/- mice demonstrate whole-brain volume reductions, ventriculomegaly and regional gray and white matter volume reductions. Comparative MRIs on 2-month-old Mbnl1-/-, Mbnl2-/- and Mbnl1-/-/Mbnl2+/- brains show genotype-specific reductions in white and gray matter volumes. In both cohorts, white matter volume reductions predominate, with Mbnl2 loss leading to more widespread alterations than Mbnl1 loss. Hippocampal volumes are susceptible to changes in either Mbnl1 or Mbnl2 levels, where both single gene and dual depletions result in comparable volume losses. In contrast, the cortex, inter/midbrain, cerebellum and hindbrain regions show both gene and dose-specific volume decreases. Our results provide a molecular explanation for phenotype intensification in congenital DM1 and the variability in the brain structural alterations reported in DM1.
Insights
Loss of Muscleblind-like proteins (Mbnl1, Mbnl2) causes brain structural defects in mice, explaining Myotonic Dystrophy Type I brain changes. White matter volume reduction is a key finding.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Myotonic Dystrophy Type I (DM1) is characterized by variable brain structural alterations of unknown cause.
- Muscleblind-like proteins (Mbnl1, Mbnl2) are implicated in DM1 pathogenesis.
Purpose of the Study:
- To investigate the role of Mbnl1 and Mbnl2 inactivation in causing brain structural defects.
- To elucidate the molecular etiology of brain alterations in DM1.
Main Methods:
- Utilized 2D FSE T2w MRI on Mbnl1 and Mbnl2 deficient mouse models.
- Analyzed whole-brain, regional gray matter, and white matter volumes in different knockout cohorts.
Main Results:
- Inactivation of Mbnl1 and Mbnl2 leads to significant whole-brain volume reductions and ventriculomegaly.
- Mbnl2 loss results in more widespread brain alterations than Mbnl1 loss, with white matter predominantly affected.
- Specific brain regions like the hippocampus, cortex, and cerebellum show gene and dose-dependent volume reductions.
Conclusions:
- Mbnl1 and Mbnl2 inactivation provide a molecular explanation for brain structural defects observed in DM1.
- These findings clarify the basis for phenotype intensification in congenital DM1 and variability in brain alterations.
