[en] BACKGROUND: Neurogenesis is stimulated in the subventricular zone (SVZ) of mice with cortical brain injuries. In most of these injuries, newly generated neuroblasts attempt to migrate toward the injury, accumulating within the corpus callosum not reaching the perilesional area.
METHODS: We use a murine model of mechanical cortical brain injury, in which we perform unilateral cortical injuries in the primary motor cortex of adult male mice. We study neurogenesis in the SVZ and perilesional area at 7 and 14 dpi as well as the expression and concentration of the signaling molecule transforming growth factor alpha (TGF-α) and its receptor the epidermal growth factor (EGFR). We use the EGFR inhibitor Afatinib to promote neurogenesis in brain injuries.
RESULTS: We show that microglial cells that emerge within the injured area and the SVZ in response to the injury express high levels of TGF-α leading to elevated concentrations of TGF-α in the cerebrospinal fluid. Thus, the number of neuroblasts in the SVZ increases in response to the injury, a large number of these neuroblasts remain immature and proliferate expressing the epidermal growth factor receptor (EGFR) and the proliferation marker Ki67. Restraining TGF-α release with a classical protein kinase C inhibitor reduces the number of these proliferative EGFR+ immature neuroblasts in the SVZ. In accordance, the inhibition of the TGF-α receptor, EGFR promotes migration of neuroblasts toward the injury leading to an elevated number of neuroblasts within the perilesional area.
CONCLUSIONS: Our results indicate that in response to an injury, microglial cells activated within the injury and the SVZ release TGF-α, activating the EGFR present in the neuroblasts membrane inducing their proliferation, delaying maturation and negatively regulating migration. The inactivation of this signaling pathway stimulates neuroblast migration toward the injury and enhances the quantity of neuroblasts within the injured area. These results suggest that these proteins may be used as target molecules to regenerate brain injuries.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Gómez Oliva, Ricardo ; Université de Liège - ULiège > GIGA > GIGA Neurosciences - Molecular Regulation of Neurogenesis ; Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain ; Instituto de Investigación e Innovación Biomédica de Cádiz, Cádiz, Spain
Geribaldi-Doldán, Noelia; Instituto de Investigación e Innovación Biomédica de Cádiz, Cádiz, Spain ; Departamento de Anatomía y Embriología Humanas, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain
Domínguez-García, Samuel; Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain ; Instituto de Investigación e Innovación Biomédica de Cádiz, Cádiz, Spain ; Department of Neuroscience, Karolinska Institutet, Biomedicum, Stockholm, Sweden
Pardillo-Díaz, Ricardo; Instituto de Investigación e Innovación Biomédica de Cádiz, Cádiz, Spain ; Hospital Universitario Puerta del Mar, Cadiz, Spain
Martínez-Ortega, Sergio; Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain ; Instituto de Investigación e Innovación Biomédica de Cádiz, Cádiz, Spain
Oliva-Montero, José M; Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain ; Instituto de Investigación e Innovación Biomédica de Cádiz, Cádiz, Spain
Pérez-García, Patricia; Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain ; Instituto de Investigación e Innovación Biomédica de Cádiz, Cádiz, Spain
García-Cózar, Francisco J; Instituto de Investigación e Innovación Biomédica de Cádiz, Cádiz, Spain ; Área de Inmunología, Universidad de Cádiz, Cádiz, Spain
Muñoz-Miranda, Juan P; Servicios Centrales de Investigación Biomédica, Universidad de Cádiz, Cádiz, Spain
Sánchez-Gomar, Ismael; Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain ; Instituto de Investigación e Innovación Biomédica de Cádiz, Cádiz, Spain
Nunez-Abades, Pedro; Instituto de Investigación e Innovación Biomédica de Cádiz, Cádiz, Spain ; Departamento de Fisiología, Universidad de Sevilla, Sevilla, Spain
Castro, Carmen ; Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain. carmen.castro@uca.es ; Instituto de Investigación e Innovación Biomédica de Cádiz, Cádiz, Spain. carmen.castro@uca.es
Language :
English
Title :
Targeting epidermal growth factor receptor to recruit newly generated neuroblasts in cortical brain injuries.
AEI - Agencia Estatal de Investigación Junta de Andalucía. Consejería de Economía, Conocimiento, Empresas y Universidad Junta de Andalucía. Consejería de Salud y Familias UCA - Universidad de Cádiz
Funding text :
Funding for open access publishing: Universidad de Cádiz/CBUA. This work was supported by the Spanish Agencia Estatal de Investigación (Grant numbers RTI-2018–099908-B-C21 granted to CC and Consejería de Economía, Conocimiento, Empresas y Universidades (Grant number FEDER-UCA18-106647). This work was financed with funds for the financing of Research and Innovation in Biomedical and Health sciences, within the framework of the Integrated Territorial Initiative 2014-2020, for the province of Cádiz. Project co-financed 80% by the European Union, within the framework of the Operational Program ERDF Andalusia 2014-2020 (Grant number ITI-Cadiz-2019–0042).We thank the Servicio de experimentación y producción animal (SEPA) de la Universidad de Cádiz as well as the Servicios Centrales de apoyo a la investigación en Ciencias de la Salud (SCICS) and Servicios centrales de Ciencia y tecnología (SC-ICYT) de la Universidad de Cádiz.
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