4.6 Article

A Disintegrin and Metalloproteinase 10 (ADAM10) Is Essential for Oligodendrocyte Precursor Development and Myelination in the Mouse Brain

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MOLECULAR NEUROBIOLOGY
卷 60, 期 3, 页码 1675-1689

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SPRINGER
DOI: 10.1007/s12035-022-03163-0

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A disintegrin and metalloproteinase 10 (ADAM10); Myelination; Oligodendrocyte precursors (OPCs); Central nervous system (CNS); Notch-1

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ADAM10 plays a crucial role in the development and myelination of oligodendrocyte precursors (OPCs) in the central nervous system (CNS) of mice. Conditional knockout of ADAM10 resulted in significant phenotypic changes, such as hair loss, reduced weight and length, and anxiety and depression-like behaviors. The loss of ADAM10 also led to a decrease in the number of OPCs and mature oligodendrocytes, as well as the inhibition of Notch-1 signaling.
A disintegrin and metalloproteinase 10 (ADAM10) plays an essential role in the regulation of survival, proliferation, migration, and differentiation of various neural cells. Nevertheless, the role of ADAM10 in oligodendrocyte precursors (OPCs) and myelination in the central nervous system (CNS) of developing and adult mouse brains is still unknown. We generated ADAM10 conditional knockout (ADAM10 cKO) mice lacking the ADAM10 gene primarily in OPCs by crossing NG2-Cre mice with ADAM10 (loxp/loxp) mice. We found that OPCs expressed ADAM10 in the mouse corpus callosum and the hippocampus. ADAM10 cKO mice showed significant loss of back hair and reduction in weight and length on postnatal (30 +/- 2.1) day, died at (65 & PLUSMN; 5) days after birth, and exhibited the anxiety and depression-like performances. Conditional knockout of ADAM10 in OPCs resulted in a prominent increase in myelination and a decrease in the number of OPCs in the corpus callosum at P30 owing to premyelination and lack of proliferation of OPCs. Moreover, the number of proliferating OPCs and mature oligodendrocytes (OLs) also decreased with age in the corpus callosum of ADAM10 cKO mice from P30 to P60. Western blot and RT-PCR results showed that the activation of Notch-1 and its four target genes, Hes1, Hes5, Hey1, and Hey2, was inhibited in the corpus callosum tissue of ADAM10 knockout mice. In our study, we provided experimental evidence to demonstrate that ADAM10 is essential for modulating CNS myelination and OPC development by activating Notch-1 signaling in the developing and adult mouse brain.

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