Mbnl1 and Mbnl2 regulate brain structural integrity in mice

• Published in: Communications biology Vol. 4; no. 1; p. 1342
• Main Authors: Sta Maria, Naomi S., Zhou, Chenyu, Lee, Se Jung, Valiulahi, Parvin, Li, Xiandu, Choi, Jongkyu, Liu, Xiaodan, Jacobs, Russell, Comai, Lucio, Reddy, Sita
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30-11-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 59; 59/36; 59/57; 631/378/2583; 64; 64/110; 64/60; 692/699/375/374; Animals; Biology; Biomedical and Life Sciences; Brain; Brain - pathology; Cerebellum; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Etiology; Female; Genotype; Genotypes; Hindbrain; Hippocampus; Life Sciences; Magnetic resonance imaging; Mesencephalon; Mice; Myotonic dystrophy; Phenotypes; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Substantia alba; Substantia grisea
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-021-02845-0

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.
Sta Maria et al. use 2D MRI to study brains from mice deficient in Mbnl1 and/or Mbnl2 as these Muscleblind-like proteins are thought to play a role in Myotonic Dystrophy Type I (DM1). They show brain region-specific reductions in white and gray matter that could help to explain the variability in the brain structural alterations reported in DM1.