Mice with 16p11.2 Deletion and Duplication Show Alterations in Biological Processes Associated with White Matter
Journal
International Journal of Molecular Sciences
Date Issued
2025-01-11
Author(s)
Tianqi Wang
Megan Sharp
Ilaria Morella
Francesco Bedogni
Riccardo Brambilla
Yasir Ahmed Syed
DOI
10.3390/ijms26020573
Abstract
Deletion and duplication in the human 16p11.2 chromosomal region are closely
linked to neurodevelopmental disorders, specifically autism spectrum disorder. Data
from neuroimaging studies suggest white matter microstructure aberrations across these
conditions. In 16p11.2 deletion and duplication carriers, potential gene dosage effects may
impact white matter organisation, contributing to phenotypes including impaired cognition.
However, the biological mechanisms underlying this white matter pathology remain
unclear. To bridge this knowledge gap, we utilised mouse models of 16p11.2 deletion
and duplication to explore changes in corpus callosum oligodendrocytes, myelination,
axon caliber, and astrocytes. Immunofluorescence staining was employed to measure
lineage and mature oligodendrocyte numbers, as well as myelin basic protein and glial
fibrillary acidic protein fluorescence intensity. Transmission electron microscopy was
utilised to evaluate axonal structural alterations related to myelin, such as myelinated axon
percentage, diameter, myelin thickness, and g-ratio. Our findings reveal changes in the
number of mature oligodendrocytes, myelination levels, axon diameter, and astrocytes
in the corpus callosum of mice with 16p11.2 deletion and duplication. Deletion mice
displayed a tendency toward reduced counts of mature oligodendrocytes and myelination
levels, while duplication mice exhibited a notable increase. Axon diameter variations
included a significant increase in axon diameter and myelin thickness in both deletion and
duplication mice, but with irregular structure in duplication mice. Variances in astrocytes
between genotypes showed significant early increases in development for both deletion and
duplication mice compared to wild-type mice, with this rise sustained in duplication mice
but significantly diminished in deletion mice at a later stage. Our research reveals changes
in the biological mechanisms impacting white matter. Comparison of reciprocal trends
in 16p11.2 deletion and duplication mice with wild-type mice suggests the possibility of
gene dosage effects. Identification of these mechanisms offers an initial step in unveiling
therapeutic targets for associated neurodevelopmental disorder phenotypes.
linked to neurodevelopmental disorders, specifically autism spectrum disorder. Data
from neuroimaging studies suggest white matter microstructure aberrations across these
conditions. In 16p11.2 deletion and duplication carriers, potential gene dosage effects may
impact white matter organisation, contributing to phenotypes including impaired cognition.
However, the biological mechanisms underlying this white matter pathology remain
unclear. To bridge this knowledge gap, we utilised mouse models of 16p11.2 deletion
and duplication to explore changes in corpus callosum oligodendrocytes, myelination,
axon caliber, and astrocytes. Immunofluorescence staining was employed to measure
lineage and mature oligodendrocyte numbers, as well as myelin basic protein and glial
fibrillary acidic protein fluorescence intensity. Transmission electron microscopy was
utilised to evaluate axonal structural alterations related to myelin, such as myelinated axon
percentage, diameter, myelin thickness, and g-ratio. Our findings reveal changes in the
number of mature oligodendrocytes, myelination levels, axon diameter, and astrocytes
in the corpus callosum of mice with 16p11.2 deletion and duplication. Deletion mice
displayed a tendency toward reduced counts of mature oligodendrocytes and myelination
levels, while duplication mice exhibited a notable increase. Axon diameter variations
included a significant increase in axon diameter and myelin thickness in both deletion and
duplication mice, but with irregular structure in duplication mice. Variances in astrocytes
between genotypes showed significant early increases in development for both deletion and
duplication mice compared to wild-type mice, with this rise sustained in duplication mice
but significantly diminished in deletion mice at a later stage. Our research reveals changes
in the biological mechanisms impacting white matter. Comparison of reciprocal trends
in 16p11.2 deletion and duplication mice with wild-type mice suggests the possibility of
gene dosage effects. Identification of these mechanisms offers an initial step in unveiling
therapeutic targets for associated neurodevelopmental disorder phenotypes.
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