RT journal article
T1 Specific inhibition of ADAM17/TACE promotes neurogenesis in the injured motor cortex
A1 Geribaldi Doldán, Noelia
A1 Carrasco Viñuela, Manuel
A1 Murillo Carretero, Maribel
A1 Domínguez García, Samuel
A1 García Cózar, Francisco José
A1 Muñoz Miranda, Juan Pedro
A1 del Río García, Valme
A1 Verástegui Escolano, Cristina
A1 Castro González, Carmen
A2 Anatomía y Embriología Humana
A2 BiomedicinaBiotecnología y Salud Pública
K1 neurogenesis
K1 traumatic brain injury
K1 neuroblast migration
K1 ADAM17
AB Brain injuries in the adult mammalian brain are accompanied by a fast neurogenic response inside neurogenic niches. However, this response does not contribute to the generation of new neurons within damaged tissues like the cerebral cortex, which are essentially non-neurogenic. This occurs because injuries create a hostile environment that favors gliogenesis. Overexpression and sequential activation of the ADAM17/TGFα/EGFR signaling cascade are crucial for the generation of this gliogenic/non-neurogenic environment. Here, we demonstrate that chronic local infusion of a general metalloprotease inhibitor in areas of traumatic cortical injury in adult mice moderately increased the number of neuroblasts around the lesion, by facilitating the survival of neuroblasts and undifferentiated progenitors, which had migrated to the perilesional area from the subventricular zone. Next, we generated a dominant-negative version of ADAM17 metalloprotease, consisting of a truncated protein containing only the pro-domain (ADAM17-Pro). Specific inhibition of ADAM17 activity by ADAM17-Pro overexpression increased the generation of new neurons in vitro. Local overexpression of ADAM17-Pro in injured cortex in vivo, mediated by lentiviral vectors, dramatically increased the number of neuroblasts observed at the lesion 14 days after injury. Those neuroblasts were able to differentiate into cholinergic and GABAergic neurons 28 days after injury. We conclude that ADAM17 is a putative target to develop new therapeutic tools for the treatment of traumatic brain injury.
PB Nature Publishing Group
SN 2041-4889
YR 2018
FD 2018-09
LK http://hdl.handle.net/10498/30595
UL http://hdl.handle.net/10498/30595
LA eng
DS Repositorio Institucional de la Universidad de Cádiz
RD 06-nov-2026