RESUMO
The architecture of the neurovascular unit (NVU) is controlled by the communication of neurons, glia, and vascular cells. We found that the neuronal guidance cue reelin possesses proangiogenic activities that ensure the communication of endothelial cells (ECs) with the glia to control neuronal migration and the establishment of the blood-brain barrier in the mouse brain. Apolipoprotein E receptor 2 (ApoER2) and Disabled1 (Dab1) expressed in ECs are required for vascularization of the retina and the cerebral cortex. Deletion of Dab1 in ECs leads to a reduced secretion of laminin-α4 and decreased activation of integrin-ß1 in glial cells, which in turn control neuronal migration and barrier properties of the NVU. Thus, reelin signaling in the endothelium is an instructive and integrative cue essential for neuro-glia-vascular communication.
Assuntos
Comunicação Celular , Córtex Cerebral/irrigação sanguínea , Endotélio Vascular/fisiologia , Neovascularização Fisiológica , Proteínas do Tecido Nervoso/metabolismo , Neuroglia/fisiologia , Neurônios/fisiologia , Vasos Retinianos/fisiologia , Animais , Barreira Hematoencefálica/citologia , Barreira Hematoencefálica/fisiologia , Moléculas de Adesão Celular Neuronais/genética , Moléculas de Adesão Celular Neuronais/metabolismo , Movimento Celular , Endotélio Vascular/metabolismo , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Feminino , Deleção de Genes , Integrina beta1/metabolismo , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas Relacionadas a Receptor de LDL/metabolismo , Laminina/metabolismo , Masculino , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Neuroglia/citologia , Neuroglia/metabolismo , Neurônios/metabolismo , Proteína Reelina , Vasos Retinianos/citologia , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Transdução de SinaisRESUMO
Tumours exploit their hypoxic microenvironment to induce a more aggressive phenotype, while curtailing the growth-inhibitory effects of hypoxia through mechanisms that are poorly understood. The prolyl hydroxylase PHD3 is regulated by hypoxia and plays an important role in tumour progression. Here we identify PHD3 as a central regulator of epidermal growth factor receptor (EGFR) activity through the control of EGFR internalization to restrain tumour growth. PHD3 controls EGFR activity by acting as a scaffolding protein that associates with the endocytic adaptor Eps15 and promotes the internalization of EGFR. In consequence, loss of PHD3 in tumour cells suppresses EGFR internalization and hyperactivates EGFR signalling to enhance cell proliferation and survival. Our findings reveal that PHD3 inactivation provides a novel route of EGFR activation to sustain proliferative signalling in the hypoxic microenvironment.