Abnormal astrocyte development and neuronal death in mice lacking the epidermal growth factor receptor

Kornblum, Harley I.; Hussain, Raymond; Wiesen, Jane; Miettinen, Päivi J.; Zurcher, Shelley D.; Chow, Kit May; Derynck, Rik; Werb, Zena

doi:10.1002/(sici)1097-4547(19980915)53:6<697::aid-jnr8>3.3.co;2-m

Cited by 7 publications

(4 citation statements)

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“…For example, severely abnormal placental development and immaturity of the lung were observed in Egfr-knockout mice, leading to spontaneous embryonic or perinatal death. Impaired neural development with progressive neurodegeneration resulting from elevated apoptosis of neural cells in the brain was also observed in these mice (129,145,203). These genetic studies demonstrate that Egfr is indispensable during development.…”

Section: A Physiological Signaling Of the Erbb Familymentioning

confidence: 81%

Acquired Resistance to Clinical Cancer Therapy: A Twist in Physiological Signaling

Wicki

Mandalà

Massi

et al. 2016

Physiological Reviews

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Although modern therapeutic strategies have brought significant progress to cancer care in the last 30 years, drug resistance to targeted monotherapies has emerged as a major challenge. Aberrant regulation of multiple physiological signaling pathways indispensable for developmental and metabolic homeostasis, such as hyperactivation of pro-survival signaling axes, loss of suppressive regulations, and impaired functionalities of the immune system, have been extensively investigated aiming to understand the diversity of molecular mechanisms that underlie cancer development and progression. In this review, we intend to discuss the molecular mechanisms of how conventional physiological signal transduction confers to acquired drug resistance in cancer patients. We will particularly focus on protooncogenic receptor kinase inhibition-elicited tumor cell adaptation through two major core downstream signaling cascades, the PI3K/Akt and MAPK pathways. These pathways are crucial for cell growth and differentiation and are frequently hyperactivated during tumorigenesis. In addition, we also emphasize the emerging roles of the deregulated host immune system that may actively promote cancer progression and attenuate immunosurveillance in cancer therapies. Understanding these mechanisms may help to develop more effective therapeutic strategies that are able to keep the tumor in check and even possibly turn cancer into a chronic disease.

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Section: A Physiological Signaling Of the Erbb Familymentioning

confidence: 81%

Acquired Resistance to Clinical Cancer Therapy: A Twist in Physiological Signaling

Wicki

Mandalà

Massi

et al. 2016

Physiological Reviews

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“…Mice surviving the first postnatal week are growth retarded and show abnormalities in skin 12, 14, 15, bone 16, 17, intestine 12 and brain 13, 15, 18 development, proving an essential role for EGFR signaling in multiple organs. Most EGFR knock‐out mice die before weaning age, although in very rare cases the mice can survive up to 1 month 12, 14.…”

Section: Introductionmentioning

confidence: 99%

“…Most EGFR knock‐out mice die before weaning age, although in very rare cases the mice can survive up to 1 month 12, 14. Embryonic brain development proceeds inconspicuously in EGFR knock‐out mice, but postnatally a massive degeneration of the cerebral cortex and the olfactory bulbs can be observed, which is characterized by apoptotic death of neurons as well as astrocytes 13, 18. Degenerative processes can also be detected in the thalamus but thalamic astrocytes do not seem to be affected by apoptosis and can actively respond to the neuronal degeneration by inducing reactive gliosis.…”

Section: Introductionmentioning

confidence: 99%

Impaired neural stem cell expansion and hypersensitivity to epileptic seizures in mice lacking the EGFR in the brain

et al. 2018

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Mice lacking the epidermal growth factor receptor (EGFR) develop an early postnatal degeneration of the frontal cortex and olfactory bulbs and show increased cortical astrocyte apoptosis. The poor health and early lethality of EGFR−/− mice prevented the analysis of mechanisms responsible for the neurodegeneration and function of the EGFR in the adult brain. Here, we show that postnatal EGFR‐deficient neural stem cells are impaired in their self‐renewal potential and lack clonal expansion capacity in vitro. Mice lacking the EGFR in the brain (EGFRΔbrain) show low penetrance of cortical degeneration compared to EGFR−/− mice despite genetic recombination of the conditional allele. Adult EGFRΔ mice establish a proper blood–brain barrier and perform reactive astrogliosis in response to mechanical and infectious brain injury, but are more sensitive to Kainic acid‐induced epileptic seizures. EGFR‐deficient cortical astrocytes, but not midbrain astrocytes, have reduced expression of glutamate transporters Glt1 and Glast, and show reduced glutamate uptake in vitro, illustrating an excitotoxic mechanism to explain the hypersensitivity to Kainic acid and region‐specific neurodegeneration observed in EGFR‐deficient brains.

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“…Changes in the expression of growth factor receptors subsequently result in the specification of astroglial cells (see also Table 1). Here, it has been shown that the expression of the epidermal growth factor (EGF)-Receptor seems to be necessary for normal astrocyte development (Kornblum et al, 1998). While initial PDGF and FGF2 signals form these cells the cells themselves turn to a PDGF-R negative precursor cell (see also Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Astrocytes as a Source for Extracellular Matrix Molecules and Cytokines

Wiese¹,

Karus²,

Faissner³

2012

Front. Pharmacol.

220

185

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Research of the past 25 years has shown that astrocytes do more than participating and building up the blood-brain barrier and detoxify the active synapse by reuptake of neurotransmitters and ions. Indeed, astrocytes express neurotransmitter receptors and, as a consequence, respond to stimuli. Within the tripartite synapse, the astrocytes owe more and more importance. Besides the functional aspects the differentiation of astrocytes has gained a more intensive focus. Deeper knowledge of the differentiation processes during development of the central nervous system might help explaining and even help treating neurological diseases like Alzheimer’s disease, Amyotrophic lateral sclerosis, Parkinsons disease, and psychiatric disorders in which astrocytes have been shown to play a role. Specific differentiation of neural stem cells toward the astroglial lineage is performed as a multi-step process. Astrocytes and oligodendrocytes develop from a multipotent stem cell that prior to this has produced primarily neuronal precursor cells. This switch toward the more astroglial differentiation is regulated by a change in receptor composition on the cell surface and responsiveness to Fibroblast growth factor and Epidermal growth factor (EGF). The glial precursor cell is driven into the astroglial direction by signaling molecules like Ciliary neurotrophic factor, Bone Morphogenetic Proteins, and EGF. However, the early astrocytes influence their environment not only by releasing and responding to diverse soluble factors but also express a wide range of extracellular matrix (ECM) molecules, in particular proteoglycans of the lectican family and tenascins. Lately these ECM molecules have been shown to participate in glial development. In this regard, especially the matrix protein Tenascin C (Tnc) proved to be an important regulator of astrocyte precursor cell proliferation and migration during spinal cord development. Nevertheless, ECM molecules expressed by reactive astrocytes are also known to act mostly in an inhibitory fashion under pathophysiological conditions. Thus, we further summarize resent data concerning the role of chondroitin sulfate proteoglycans and Tnc under pathological conditions.

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Abnormal astrocyte development and neuronal death in mice lacking the epidermal growth factor receptor

Cited by 7 publications

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Acquired Resistance to Clinical Cancer Therapy: A Twist in Physiological Signaling

Acquired Resistance to Clinical Cancer Therapy: A Twist in Physiological Signaling

Impaired neural stem cell expansion and hypersensitivity to epileptic seizures in mice lacking the EGFR in the brain

Astrocytes as a Source for Extracellular Matrix Molecules and Cytokines

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