Oligodendrocyte Regeneration and CNS Remyelination Require TACE/ADAM17.
The identification of the molecular network that supports oligodendrocyte (OL) regeneration under demyelinating conditions has been a primary goal for regenerative medicine in demyelinating disorders. We recently described an essential function for TACE/ADAM17 in regulating oligodendrogenesis during postnatal myelination, but it is unknown whether this protein also plays a role in OL regeneration and remyelination under demyelinating conditions. By using genetic mouse models to achieve selective gain- or loss-of-function of TACE or EGFR in OL lineage cells in vivo, we found that TACE is critical for EGFR activation in OLs following demyelination, and therefore, for sustaining OL regeneration and CNS remyelination. TACE deficiency in oligodendrocyte progenitor cells following demyelination disturbs OL lineage cell expansion and survival, leading to a delay in the remyelination process. EGFR overexpression in TACE deficient OLs in vivo restores OL development and postnatal CNS myelination, but also OL regeneration and CNS remyelination following demyelination. Our study reveals an essential function of TACE in supporting OL regeneration and CNS remyelination that may contribute to the design of new strategies for therapeutic intervention in demyelinating disorders by promoting oligodendrocyte regeneration and myelin repair.



Oligodendrocyte (OL) regeneration has emerged as a promising new approach for the treatment of demyelinating disorders. By using genetic mouse models to selectively delete TACE expression in oligodendrocyte progenitors cells (OPs), we found that TACE/ADAM17 is required for supporting OL regeneration following demyelination. TACE genetic depletion in OPs abrogates EGFR activation in OL lineage cells, and perturbs cell expansion and survival, blunting the process of CNS remyelination. Moreover, EGFR overexpression in TACE-deficient OPs in vivo overcomes the defects in OL development during postnatal development but also OL regeneration during CNS remyelination. Our study identifies TACE as an essential player in OL regeneration that may provide new insights in the development of new strategies for promoting myelin repair in demyelinating disorders.
Department of Pharmacological Sciences, Centers for Molecular Medicine, Stony Brook University, SUNY, Stony Brook, New York 11794, Adan.Aguirre@StonyBrook.edu Javier.PalazuelosDiego@StonyBrook.edu.
Javier
0000-0002-0409-1398
J
Palazuelos
Department of Pharmacological Sciences, Centers for Molecular Medicine, Stony Brook University, SUNY, Stony Brook, New York 11794.
Michael
M
Klingener
Department of Pathology, University of Washington, Seattle, Washington 98195, and.
Elaine W
EW
Raines
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109.
Howard C
HC
Crawford
Department of Pharmacological Sciences, Centers for Molecular Medicine, Stony Brook University, SUNY, Stony Brook, New York 11794, Adan.Aguirre@StonyBrook.edu Javier.PalazuelosDiego@StonyBrook.edu.
Adan
A
Aguirre
D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase / Q000235:genetics / Q000378:metabolism; D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D000818:Animals; D000941:Antigens / Q000235:genetics / Q000378:metabolism; D019070:Cell Lineage / Q000187:drug effects / Q000235:genetics; D002490:Central Nervous System / Q000473:pathology*; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000473:pathology*; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000473:pathology*; D009836:Oligodendroglia / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects / Q000502:physiology*; D000099216:Chondroitin Sulfate Proteoglycan 4
D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase; D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000941:Antigens; D066246:ErbB Receptors; D008164:Luminescent Proteins; D011509:Proteoglycans; D020796:Receptor, Platelet-Derived Growth Factor alpha; D000099216:Chondroitin Sulfate Proteoglycan 4; C413663:fluorescent protein 583; C541485:EGFR protein, mouse; C571338:Cnp protein, mouse; C000606463:Adam17 protein, mouse
ADAM17; EGFR; TACE; oligodendrocyte precursor; remyelination