A strain-independent postnatal neurodegeneration in mice lacking the EGF receptor

Sibilia, Maria; Steinbach, Joachim P.; Stingl, Laura; Aguzzi, Adriano; Wagner, Erwin F.

doi:10.1093/emboj/17.3.719

Cited by 287 publications

(226 citation statements)

References 59 publications

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“…We have previously reported that the thalamus of EGFR −/− mice was also affected by degenerative processes, which are accompanied by massive astrogliosis 13. Neither neuronal loss nor increased astrogliosis could be observed in the thalami of EGFR ΔNes and EGFR ΔGfap mice, however, closer inspection of the hippocampi revealed the presence of nests of ectopic neurons in the white matter both in EGFR Δ mice (Fig.…”

Section: Resultsmentioning

confidence: 73%

“…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%

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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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Section: Resultsmentioning

confidence: 73%

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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“…EGFR-deficient mice die from preimplantation to 3 weeks postnatally depending on genetic background and show defects in cell proliferation, differentiation and migration in a wide range of tissues including skin, central nervous system, intestines, lung, liver, kidneys, placenta, palate and facies [113][114][115][116]. Strain-independent neurodegeneration within the frontal cortex, olfactory bulbs, and thalamus occurs postnatally in EGFR-deficient mice as well [117,118].…”

Section: Erbb Members In Mammalian Developmentmentioning

confidence: 99%

The epidermal growth factor receptor family: Biology driving targeted therapeutics

Wieduwilt

Moasser

2008

Cell. Mol. Life Sci.

636

503

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The epidermal growth factor family of receptor tyrosine kinases (ErbBs) plays essential roles in regulating cell proliferation, survival, differentiation and migration. The ErbB receptors carry out both redundant and restricted functions in mammalian development and in the maintenance of tissues in the adult mammal. Loss of regulation of the ErbB receptors underlies many human diseases, most notably cancer. Our understanding of the function and complex regulation of these receptors has fueled the development of targeted therapeutic agents for human malignancies in the last 15 years. Here we review the biology of ErbB receptors, including their structure, signaling, regulation, and roles in development and disease, then briefly touch on their increasing roles as targets for cancer therapy.

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“…In particular, ErbB1 is enriched in GABAergic neurons and dopaminergic neurons (Gómez-Pinilla et al, 1988;Kornblum et al, 1995Kornblum et al, , 1997. Mice lacking ErbB1 exhibit abnormal cortical development, including loss of astrocytes and impaired neuronal migration (Threadgill et al, 1995;Kornblum et al, 1998;Sibilia et al, 1998). The developmental effects of ErbB1 ligands on postmitotic neurons remain to be characterized, however.…”

Section: Introductionmentioning

confidence: 99%

Transforming growth factor alpha attenuates the functional expression of AMPA receptors in cortical GABAergic neurons

Namba

Nagano

Iwakura

et al. 2006

Molecular and Cellular Neuroscience

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In the developing neocortex, brain-derived neurotrophic factor (BDNF) exerts a trophic activity to increase the expression and channel activity of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor subunits. Here, we demonstrate that the epidermal growth factor (EGF) receptor (ErbB1) ligands exert the opposite biological activity in cultured neocortical neurons. Subchronic stimulation of ErbB1 with transforming growth factor α (TGFα), EGF, or heparin-binding EGF (HB-EGF) down-regulated protein expression of the GluR1 AMPA receptor subunit in cultured neocortical neurons. In agreement, TGFα treatment decreased the B max of [ 3 H] AMPA binding and GluR1 mRNA levels. Immunocytochemistry revealed that the decrease in GluR1 was most pronounced in multipolar GABAergic neurons. To examine the physiological consequences, we recorded AMPA-evoked currents as well as miniature excitatory postsynaptic currents in morphologically identified putative GABAergic neurons in culture. Subchronic TGFα treatment decreased AMPA-triggered currents as well as the amplitude and frequency of miniature excitatory postsynaptic currents. An ErbB1 tyrosine kinase inhibitor, PD153035, inhibited the TGFα effect. Moreover, TGFα counteracted the neurotrophic activity of BDNF on AMPA receptor expression. Co-application of TGFα with BDNF blocked the BDNF-triggered up-regulation of AMPA receptor expression and currents. These observations reveal a negative regulatory activity of the ErbB1 ligand, TGFα, which reduces the input sensitivity of cortical GABAergic neurons to attenuate their inhibitory function.

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A strain-independent postnatal neurodegeneration in mice lacking the EGF receptor

Cited by 287 publications

References 59 publications

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

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

The epidermal growth factor receptor family: Biology driving targeted therapeutics

Transforming growth factor alpha attenuates the functional expression of AMPA receptors in cortical GABAergic neurons

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