Oligodendrocyte precursor hypercellularity and abnormal retina development in mice overexpressing PDGF‐B in myelinating tracts

Forsberg-Nilsson, Karin; Erlandsson, Anna; Zhang, Xiao Qun; Ueda, Hideho; Svensson, Kristian; Nistér, Monica; Trapp, Bruce D.; Peterson, Alan C.; Westermark, Bengt

doi:10.1002/glia.10191

Cited by 18 publications

(10 citation statements)

References 38 publications

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“…Here, we report a line of GFAP/hPDGFB mice that primarily developed spinal CNS malignancies. Also, both transgenic models we have presented had retinal alterations (data not shown), a finding consistent with the work of others (36,39). The pattern of tumorigenesis, and our characterization of high levels of hPDGF expression in spinal tissue, suggest that differential transgene expression underlies the phenotypes we observed.…”

Section: Discussionsupporting

confidence: 91%

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Spinal Glioma: Platelet-Derived Growth Factor B–Mediated Oncogenesis in the Spinal Cord

et al. 2008

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Human platelet-derived growth factor B (hPDGFB) has been characterized in vitro and shown to mediate numerous cellular responses including glial proliferation and differentiation. Expression of PDGFB is thought to be important in the pathogenesis of glioma and several animal models of cerebral glioma based on PDGF expression have been described. To examine whether PDGF could contribute to the pathogenesis of spinal cord glioma, we developed transgenic mice that express hPDGFB under the control of a tetracyclineresponsive element (TRE/hPDGFB). These TRE/hPDGFB mice were mated with transgenic mice expressing the tetracycline transcriptional activator (tet-off), tTA, regulated by the human glial fibrillary acidic protein (GFAP) promoter and exhibiting uniquely strong promoter activity in the spinal cord. These transgenic mice (GFAP/tTA:TRE/hPDGFB) expressed hPDGFB in GFAP-expressing glia in a manner responsive to doxycycline administration. Without doxycycline, almost all GFAP/tTA:TRE/hPDGFB mice developed spinal cord neoplasms resembling human mixed oligoastrocytoma. Tumorigenesis in these animals was suppressed by doxycycline. To further examine the importance of PDGFB in mouse primary intramedullary spinal cord tumors, we also created transgenic mice expressing hPDGFB under the control of the human GFAP promoter (GFAP/hPDGFB). These GFAP/ hPDGFB mice also developed spinal oligoastrocytoma. PDGFB can mediate the development of mouse spinal tumors that are histologically and pathologically indistinguishable from primary intramedullary spinal tumors of humans and may provide opportunities for both novel insights into the pathogenesis of these tumors and the development of new therapeutics. [Cancer Res 2008;68(20):8507-15]

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Section: Discussionsupporting

confidence: 91%

“…Others have explored the in vivo activity of PDGF ligands in transgenic animals, targeting the transgene to other tissues (34)(35)(36). Two independent models were developed.…”

Section: Discussionmentioning

confidence: 99%

Spinal Glioma: Platelet-Derived Growth Factor B–Mediated Oncogenesis in the Spinal Cord

et al. 2008

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“…It is known that PDGF-B, the endogenous ligand of PDGFRβ, is highly expressed by microglia [21] and has an important role in regulating retinal capillary physiology [22]. These data indicate that CML might influence microglial PDGF-B production and, consequently, affect pericyte function via the PDGF-B receptor PDGFRβ.…”

Section: Resultsmentioning

confidence: 92%

Dietary sugars, not lipids, drive hypothalamic inflammation

Gao

Bielohuby

Fleming

et al. 2017

Molecular Metabolism

100

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ObjectiveThe hypothalamus of hypercaloric diet-induced obese animals is featured by a significant increase of microglial reactivity and its associated cytokine production. However, the role of dietary components, in particular fat and carbohydrate, with respect to the hypothalamic inflammatory response and the consequent impact on hypothalamic control of energy homeostasis is yet not clear.MethodsWe dissected the different effects of high-carbohydrate high-fat (HCHF) diets and low-carbohydrate high-fat (LCHF) diets on hypothalamic inflammatory responses in neurons and non-neuronal cells and tested the hypothesis that HCHF diets induce hypothalamic inflammation via advanced glycation end-products (AGEs) using mice lacking advanced glycation end-products (AGEs) receptor (RAGE) and/or the activated leukocyte cell-adhesion molecule (ALCAM).ResultsWe found that consumption of HCHF diets, but not of LCHF diets, increases microgliosis as well as the presence of N(ε)-(Carboxymethyl)-Lysine (CML), a major AGE, in POMC and NPY neurons of the arcuate nucleus. Neuron-secreted CML binds to both RAGE and ALCAM, which are expressed on endothelial cells, microglia, and pericytes. On a HCHF diet, mice lacking the RAGE and ALCAM genes displayed less microglial reactivity and less neovasculature formation in the hypothalamic ARC, and this was associated with significant improvements of metabolic disorders induced by the HCHF diet.ConclusionsCombined overconsumption of fat and sugar, but not the overconsumption of fat per se, leads to excessive CML production in hypothalamic neurons, which, in turn, stimulates hypothalamic inflammatory responses such as microgliosis and eventually leads to neuronal dysfunction in the control of energy metabolism.

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“…The hypothesis that the differential expression of igf-1 and pdgfb in the E/F-less group is important to maintain cell survival is in agreement with the proportion of TUNEL positive cells (only 5%, for both groups). It is also known that PDGF influences the generation of neurons and glia during embryogenesis and in early postnatal life (Forsberg-Nilsson et al 2003). Again, it can be related to the decreased expression of gfap and nestin.…”

Section: Discussionmentioning

confidence: 99%

Effects of FGF-2 and EGF removal on the differentiationof mouse neural precursor cells

Schwindt

Motta

et al. 2009

An. Acad. Bras. Ciênc.

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Cell therapy for neurological disorders has advanced, and neural precursor cells (NPC) may become the ideal candidates for neural transplantation in a wide range of diseases. However, additional work has to be done to determine either the ideal culture environment for NPC expansion in vitro, without altering their plasticity, or the FGF-2 and EGF mechanisms of cell signaling in neurospheres growth, survival and differentiation. In this work we evaluated mouse neurospheres cultured with and without FGF-2 and EGF containing medium and showed that those growth factors are responsible for NPC proliferation. It is also demonstrated that endogenous production of growth factors shifts from FGF-2 to IGF-1/PDGFb upon EGF and FGF-2 withdrawal. Mouse NPC cultured in suspension showed different patterns of neuronal localization (core versus shell) for both EGF and FGF-2 withdrawal and control groups. Taken together, these results show that EGF and FGF-2 removal play an important role in NPC differentiation and may contribute to a better understanding of mechanisms of NPC differentiation. Our findings suggest that depriving NPC of growth factors prior to grafting might enhance their chance to effectively integrate into the host.

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Oligodendrocyte precursor hypercellularity and abnormal retina development in mice overexpressing PDGF‐B in myelinating tracts

Cited by 18 publications

References 38 publications

Spinal Glioma: Platelet-Derived Growth Factor B–Mediated Oncogenesis in the Spinal Cord

Spinal Glioma: Platelet-Derived Growth Factor B–Mediated Oncogenesis in the Spinal Cord

Dietary sugars, not lipids, drive hypothalamic inflammation

Effects of FGF-2 and EGF removal on the differentiationof mouse neural precursor cells

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