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ABSTRACT: Anaplastic gliomas, the most common and malignant of primary brain tumors, frequently contain activating mutations and amplifications in promigratory signal transduction pathways. However, targeting these pathways with individual signal transduction inhibitors does not appreciably reduce tumor invasion, because these pathways are redundant; blockade of any one pathway can be overcome by stimulation of another. This implies that a more effective approach would be to target a component at which these pathways converge. In this study, we have investigated whether the molecular motor myosin II represents such a target by examining glioma invasion in a series of increasingly complex models that are sensitive to platelet-derived growth factor, epidermal growth factor, or both. Our results lead to two conclusions. First, malignant glioma cells are stimulated to invade brain through the activation of multiple signaling cascades not accounted for in simple in vitro assays. Second, even though there is a high degree of redundancy in promigratory signaling cascades in gliomas, blocking tumor invasion by directly targeting myosin II remains effective. Our results thus support our hypothesis that myosin II represents a point of convergence for signal transduction pathways that drive glioma invasion and that its inhibition cannot be overcome by other motility mechanisms.
Molecular biology of the cell 01/2012; 23(4):533-42. · 5.98 Impact Factor
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ABSTRACT: Gliogenesis requires the careful orchestration of migration, differentiation, and proliferation of progenitors. Signaling through the epidermal growth factor receptor (EGFR) has been implicated in regulating these processes in a variety of cell types, including neural progenitors. By retroviral infection, we constitutively expressed an EGFR-GFP fusion protein in white matter glial progenitors at postnatal day 3 of the rat forebrain in vivo and analyzed the development of these cells over the subsequent 15 weeks. EGFR-GFP+ cells remained proliferative and migratory, gradually populating the brains ipsilateral and contralateral to the side of viral infection, but never differentiated into mature glia. The accumulation of these cells doubled the total cell density in white matter and led to a 10-fold increase in the abundance of glial progenitors, giving rise to a progenitor "hyperplasia." The marker profile of infected cells, NG2+, olig2+, PDGFR-alpha+, nestin+, GFAP-, and CC1-, indicated a close resemblance to oligodendrocyte progenitors. Positive immunostaining for phosphorylated EGFR colocalized with punctate accumulation of EGFR-GFP, indicating that a subset of receptors was engaged in active signaling. Furthermore, EGF was required to observe phospho-tyrosine EGFR immunostaining of glial progenitors in culture. These observations suggest that constitutive EGFR expression can inhibit glial differentiation, but requires ligand as well.
Journal of Neuroscience 02/2008; 28(4):914-22. · 7.11 Impact Factor
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ABSTRACT: Coordinated production and remodeling of the extracellular matrix is essential during development. It is of particular importance for skeletogenesis, as the ability of cartilage and bone to provide structural support is determined by the composition and organization of the extracellular matrix. Connective tissue growth factor (CTGF, CCN2) is a secreted protein containing several domains that mediate interactions with growth factors, integrins and extracellular matrix components. A role for CTGF in extracellular matrix production is suggested by its ability to mediate collagen deposition during wound healing. CTGF also induces neovascularization in vitro, suggesting a role in angiogenesis in vivo. To test whether CTGF is required for extracellular matrix remodeling and/or angiogenesis during development, we examined the pattern of Ctgf expression and generated Ctgf-deficient mice. Ctgf is expressed in a variety of tissues in midgestation embryos, with highest levels in vascular tissues and maturing chondrocytes. We confirmed that CTGF is a crucial regulator of cartilage extracellular matrix remodeling by generating Ctgf(-/-) mice. Ctgf deficiency leads to skeletal dysmorphisms as a result of impaired chondrocyte proliferation and extracellular matrix composition within the hypertrophic zone. Decreased expression of specific extracellular matrix components and matrix metalloproteinases suggests that matrix remodeling within the hypertrophic zones in Ctgf mutants is defective. The mutant phenotype also revealed a role for Ctgf in growth plate angiogenesis. Hypertrophic zones of Ctgf mutant growth plates are expanded, and endochondral ossification is impaired. These defects are linked to decreased expression of vascular endothelial growth factor (VEGF) in the hypertrophic zones of Ctgf mutants. These results demonstrate that CTGF is important for cell proliferation and matrix remodeling during chondrogenesis, and is a key regulator coupling extracellular matrix remodeling to angiogenesis at the growth plate.
Development 07/2003; 130(12):2779-91. · 6.60 Impact Factor
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ABSTRACT: In the olfactory epithelium (OE), generation of new neurons by neuronal progenitors is inhibited by a signal from neurons themselves. Here we provide evidence that this feedback inhibitory signal is growth and differentiation factor 11 (GDF11). Both GDF11 and its receptors are expressed by OE neurons and progenitors, and GDF11 inhibits OE neurogenesis in vitro by inducing p27(Kip1) and reversible cell cycle arrest in progenitors. Mice lacking functional GDF11 have more progenitors and neurons in the OE, whereas mice lacking follistatin, a GDF11 antagonist, show dramatically decreased neurogenesis. This negative autoregulatory action of GDF11 is strikingly like that of its homolog, GDF8/myostatin, in skeletal muscle, suggesting that similar strategies establish and maintain proper cell number during neural and muscular development.
Neuron 02/2003; 37(2):197-207. · 14.74 Impact Factor
