1 Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
2 Department of Physiology, McGill University, Montreal, Quebec, Canada.
3 Department of Pharmacology & Therapeutics, McGill University, Montreal, Quebec, Canada.
4 Integrated Program in Neuroscience, McGill University, Montréal, Quebec, Canada.
5 Université Côte d'azur, LJAD, CNRS UMR7351, Nice, France.
6 Institute of Biomedical Engineering, Ecole Polytechnique de Montreal, Montreal, Quebec, Canada.
7 Department of Cell and Developmental Biology, State University of New York Upstate Medical University, Syracuse, New York, USA.
8 Department of Neuroscience and Physiology, State University of New York Upstate Medical University, Syracuse, New York, USA.
9 Department of Chemistry, Université de Montréal, Montreal, Quebec, Canada.
10 Department of Chemistry and Biochemistry, Concordia University, Montreal, Quebec, Canada.
11 Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut, USA.
12 Institute for Systems Genomics, University of Connecticut, Storrs, Connecticut, USA.
13 The Connecticut Institute for Brain and Cognitive Sciences, University of Connecticut, Storrs, Connecticut, USA.
14 Department of Neurobiology Research, Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark.
15 McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, Montreal, Quebec, Canada.
16 Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
17 Department of Biomedical Engineering, McGill University, Montreal, Quebec, Canada.
18 Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
19 Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
20 Mount Sinai Hospital, Lunenfeld-Tanenbaum and Toronto General Hospital Research Institutes, Toronto, Ontario, Canada.
21 Gerald Bronfman Department of Oncology, McGill University, Quebec, Canada.

Myelin basic protein (Mbp) is essential for both elaboration and maintenance of CNS myelin, and its reduced accumulation results in hypomyelination. How different Mbp mRNA levels affect myelin dimensions across the lifespan and how resident glial cells may respond to such changes are unknown. Here, to investigate these questions, we used enhancer-edited mouse lines that accumulate Mbp mRNA levels ranging from 8% to 160% of wild type. In young mice, reduced Mbp mRNA levels resulted in corresponding decreases in Mbp protein accumulation and myelin sheath thickness, confirming the previously demonstrated rate-limiting role of Mbp transcription in the control of initial myelin synthesis. However, despite maintaining lower line specific Mbp mRNA levels into old age, both Mbp protein levels and myelin thickness improved or fully normalized at rates defined by the relative Mbp mRNA level. Sheath length, in contrast, was affected only when mRNA levels were very low, demonstrating that sheath thickness and length are not equally coupled to Mbp mRNA level. Striking abnormalities in sheath structure also emerged with reduced mRNA levels. Unexpectedly, an increase in the density of all glial cell types arose in response to reduced Mbp mRNA levels. This investigation extends understanding of the role Mbp plays in myelin sheath elaboration, architecture, and plasticity across the mouse lifespan and illuminates a novel axis of glial cell crosstalk.