Transforming growth factor-α (TGF-α) and epidermal growth factor-receptor (EGF-R) immunoreactivity in normal and pathologic brain

Ferrer, Isidre; Alcántara, Soledad; Ballabriga, Jordi; Olivé, Montse; Blanco, Rosa; Rivera, Rosa María Baños; Carmona, Margarita; Berruezo, Meritxell; Pitarch, Silvia; Planas, Anna M.

doi:10.1016/0301-0082(96)00009-3

Cited by 89 publications

(49 citation statements)

References 104 publications

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“…In a broad range of CNS insults including ischemia [31][32][33], excitotoxic lesions [34], axotomy [35], and entorhinal ablation [36], de novo EGFR expression and rapid upregulation of the EGFR ligands TGF-a or heparin-binding EGF-like growth factor (HB-EGF) have been reported in local neurons and astrocytes [31,33,34]. Similar alterations have also been demonstrated in patient brains following stroke [37] or in brains of patients with Alzheimer's disease [38]. Excessive activation of the intracellular signaling pathways initiated by EGFR in the damaged nervous tissue may be responsible for preventing the generation of new neurons, and therefore, the functional recovery.…”

Section: Introductionmentioning

confidence: 78%

ADAM-17/Tumor Necrosis Factor-α-Converting Enzyme Inhibits Neurogenesis and Promotes Gliogenesis from Neural Stem Cells

et al. 2011

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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-a (TGF-a) release. These results suggested that metalloprotease-dependent EGFRligand 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-a 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.

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Section: Introductionmentioning

confidence: 78%

ADAM-17/Tumor Necrosis Factor-α-Converting Enzyme Inhibits Neurogenesis and Promotes Gliogenesis from Neural Stem Cells

et al. 2011

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“…Growth factors that are secreted by endothelial cells (Gama Sosa et al, 2007;Rosenstein and Krum, 2006) as well as by other glial cells (Aschner, 1996;Suzumura et al, 2006;Sen and Levison, 2006) during development and under pathological conditions (Ferrer et al, 1996;Lisovoski et al, 1997;Jin et al, 2002;Covey and Levison, 2007) are crucial regulators of progenitor cell mobilization. Previous reports demonstrated upregulation of several growth factors in the CC after demyelination, including HB-EGF and TGF-alpha (Ferrer et al, 1996;Lisovoski et al, 1997;Aguirre et al, 2007). In the present study, we extended the analysis of these growth factors under pathological conditions to include the SVZ itself, which is a neurogenic brain region outside of the area of demyelinated lesion itself, and is a rich source of NG2 + cells.…”

Section: Discussionmentioning

confidence: 99%

Reduced EGFR signaling in progenitor cells of the adult subventricular zone attenuates oligodendrogenesis after demyelination

Aguirre

Gallo

2007

Neuron Glia Biol.

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Neural progenitor cells expressing the NG2 proteoglycan are found in different regions of the adult mammalian brain, where they display distinct morphologies and proliferative rates. In the developing postnatal and adult mouse, NG2 + cells represent a major cell population of the subventricular zone (SVZ). NG2 + cells divide in the anterior and lateral region of the SVZ, and are stimulated to proliferate and migrate out of the SVZ by focal demyelination of the corpus callosum (CC). Many NG2 + cells are labeled by GFP-retrovirus injection into the adult SVZ, demonstrating that NG2 + cells actively proliferate under physiological conditions and after demyelination. In the wa2 mouse, which is characterized by reduced EGFR signaling, NG2 + cell proliferation, under normal physiological conditions and after focal demyelination, is significantly attenuated. This results in reduced SVZ-to-lesion migration of NG2 + cells and oligodendrogenesis in the lesion. Expression of VEGF and EGFR ligands, such as HB-EGF and TGF-alpha, is upregulated in the SVZ after focal demyelination of the CC. EGF-induced oligodendrogenesis and myelin protein expression in cultured wild-type SVZ cells were significantly attenuated in wa2 SVZ cells. Our results demonstrate that the NG2 + cell response in the SVZ and their subsequent differentiation in CC after focal demyelination are dependent upon EGFR signaling.

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“…EGFR (HER, belongs to a family of transmembrane receptors with intrinsic tyrosine kinase activity. Rapid upregulation of EGFR and its ligands occurs in astrocytes after ischemia (Planas et al, 1998;Jin et al, 2002), axotomy (Lisovoski et al, 1997), electrolytic lesion (Junier et al, 1993), and entorhinal ablation ; in the damaged regions of brains in patients after stroke (Ferrer et al, 1996) or with Alzheimer's disease (Birecree et al, 1988); and in astrocytes of optic nerves in patients with glaucoma (Liu and Neufeld, 2003). Approximately one-third of glioblastomas have EGFR amplifications (Hayashi et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Epidermal Growth Factor Receptor Activation: An Upstream Signal for Transition of Quiescent Astrocytes into Reactive Astrocytes after Neural Injury

et al. 2006

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Modulating the behaviors of reactive astrocytes is a potential therapeutic strategy for neurodegenerative diseases. We found that upregulation and activation of the epidermal growth factor receptor (EGFR) occur in astrocytes after different injuries in optic nerves in vivo. Activation of EGFR regulates genes and cellular processes representing most major markers of reactive astrocytes and genes related with glaucomatous optic neuropathy and other neural disorders. These results suggest that activation of EGFR is a common, regulatory pathway that triggers quiescent astrocytes into reactive astrocytes in response to neural injuries in the optic nerve, and perhaps other parts of the CNS. Targeting EGFR activation using an EGFR tyrosine kinase inhibitor prevents the loss of retinal ganglion cells in a model of glaucomatous optic neuropathy. Because these inhibitors are currently used clinically, our results present an approach to reactive astrocytes as a potential new target for the treatment of neurodegenerations.

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Transforming growth factor-α (TGF-α) and epidermal growth factor-receptor (EGF-R) immunoreactivity in normal and pathologic brain

Cited by 89 publications

References 104 publications

ADAM-17/Tumor Necrosis Factor-α-Converting Enzyme Inhibits Neurogenesis and Promotes Gliogenesis from Neural Stem Cells

ADAM-17/Tumor Necrosis Factor-α-Converting Enzyme Inhibits Neurogenesis and Promotes Gliogenesis from Neural Stem Cells

Reduced EGFR signaling in progenitor cells of the adult subventricular zone attenuates oligodendrogenesis after demyelination

Epidermal Growth Factor Receptor Activation: An Upstream Signal for Transition of Quiescent Astrocytes into Reactive Astrocytes after Neural Injury

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