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ADAMTS-4 in oligodendrocytes contributes to myelination with an impact on motor function
Mathilde Pruvost1, Matthieu Lépine1, Camille Leonetti1
1Normandie University, UNICAEN, INSERM, UMR-S 1237 Physiopathology and imaging of Neurological disorders, Cyceron, Caen 14000, France.
Abstract:
Myelination is a late developmental process regulated by a set of inhibitory and stimulatory factors, including extracellular matrix components. Accordingly, chondroitin sulfate proteoglycans (CSPGs) act as negative regulators of myelination processes. A disintegrin and metalloproteinase with thrombospondin motifs type 4 (ADAMTS-4) is an extracellular protease capable of degrading CSPGs. Although exogenous ADAMTS-4 has been proven to be beneficial in several models of central nervous system (CNS) injuries, the physiological functions of endogenous ADAMTS-4 remain poorly understood. We first used Adamts4/LacZ reporter mice to reveal that ADAMTS-4 is strongly expressed in the CNS, especially in the white matter, with a cellular profile restricted to mature oligodendrocytes. Interestingly, we evidenced an abnormal myelination in Adamts4-/- mice, characterized by a higher diameter of myelinated axons with a shifting g-ratio. Accordingly, lack of ADAMTS-4 is accompanied by motor deficits and disturbed nervous electrical activity. In conclusion, we demonstrate that ADAMTS-4 is a new marker of mature oligodendrocytes contributing to the myelination processes and thus to the control of motor capacities.
Insights
ADAMTS-4, an enzyme that degrades CSPGs, is crucial for normal myelination and motor function. Its absence in mice leads to abnormal myelination and motor deficits, highlighting its role in mature oligodendrocytes.
Area of Science:
- Neuroscience
- Developmental Biology
- Molecular Biology
Background:
- Myelination is a critical late developmental process influenced by extracellular matrix components.
- Chondroitin sulfate proteoglycans (CSPGs) are known inhibitors of myelination.
- ADAMTS-4 (a disintegrin and metalloproteinase with thrombospondin motifs type 4) degrades CSPGs, but its endogenous role is unclear.
Purpose of the Study:
- To investigate the physiological functions of endogenous ADAMTS-4 in the central nervous system (CNS).
- To determine the role of ADAMTS-4 in myelination and motor control.
Main Methods:
- Utilized Adamts4/LacZ reporter mice to track ADAMTS-4 expression in the CNS.
- Analyzed myelination in Adamts4 knockout (Adamts4-/-) mice.
- Assessed motor deficits and nervous electrical activity in knockout mice.
Main Results:
- ADAMTS-4 is highly expressed in CNS white matter, specifically in mature oligodendrocytes.
- Adamts4-/- mice exhibit abnormal myelination, including increased axon diameter and altered g-ratio.
- Lack of ADAMTS-4 results in motor deficits and impaired nervous electrical activity.
Conclusions:
- ADAMTS-4 is identified as a novel marker of mature oligodendrocytes.
- ADAMTS-4 plays a significant role in regulating myelination processes.
- ADAMTS-4 contributes to the control of motor capacities through its influence on myelination.
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