title: ADAM-17/tumor necrosis factor-α-converting enzyme inhibits neurogenesis and promotes gliogenesis from neural stem cells.
abstract: Neural precursor cells (NPCs) are activated in central nervous system injury. However, despite being multipotential, their progeny differentiates into astrocytes rather than neurons in situ. We have investigated the role of epidermal growth factor receptor (EGFR) in the generation of non-neurogenic conditions. Cultured mouse subventricular zone NPCs exposed to differentiating conditions for 4 days generated approximately 50% astrocytes and 30% neuroblasts. Inhibition of EGFR with 4-(3-chloroanilino)-6,7-dimethoxyquinazoline significantly increased the number of neuroblasts and decreased that of astrocytes. The same effects were observed upon treatment with the metalloprotease inhibitor galardin, N-[(2R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl]-L-tryptophan methylamide (GM 6001), which prevented endogenous transforming growth factor-α (TGF-α) release. These results suggested that metalloprotease-dependent EGFR-ligand shedding maintained EGFR activation and favored gliogenesis over neurogenesis. Using a disintegrin and metalloprotease 17 (ADAM-17) small interference RNAs transfection of NPCs, ADAM-17 was identified as the metalloprotease involved in cell differentiation in these cultures. In vivo experiments revealed a significant upregulation of ADAM-17 mRNA and de novo expression of ADAM-17 protein in areas of cortical injury in adult mice. Local NPCs, identified by nestin staining, expressed high levels of ADAM-17, as well as TGF-α and EGFR, the three molecules necessary to prevent neurogenesis and promote glial differentiation in vitro. Chronic local infusions of GM6001 resulted in a notable increase in the number of neuroblasts around the lesion. These results indicate that, in vivo, the activation of a metalloprotease, most probably ADAM-17, initiates EGFR-ligand shedding and EGFR activation in an autocrine manner, preventing the generation of new neurons from NPCs. Inhibition of ADAM-17, the limiting step in this sequence, may contribute to the generation of neurogenic niches in areas of brain damage.
authors.affiliation: Ciber of Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Romero-Grimaldi
authors.forename: Maribel
authors.initials: M
authors.lastname: Murillo-Carretero
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: López-Toledano
authors.forename: Manuel
authors.initials: M
authors.lastname: Carrasco
authors.forename: Carmen
authors.initials: C
authors.lastname: Castro
authors.forename: Carmen
authors.initials: C
authors.lastname: Estrada
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000072198:ADAM17 Protein; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000201:enzymology; D001930:Brain Injuries / Q000201:enzymology / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D004151:Dipeptides / Q000494:pharmacology; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D007150:Immunohistochemistry; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D064231:Nestin; D058953:Neural Stem Cells / Q000166:cytology* / Q000201:enzymology; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology*; D011799:Quinazolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D004151:Dipeptides; D007381:Intermediate Filament Proteins; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D011799:Quinazolines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016211:Transforming Growth Factor alpha; D020032:Tyrphostins; C101044:RTKI cpd; D066246:ErbB Receptors; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse