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

Abstract

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.

Role of EGFR in the Nervous System

“…astrocytes ( Figure 4A). These results demonstrate the importance of EGFR in NSCs selfrenewal and that loss of EGFR signaling in cells derived from SVZ leads them to differentiate preferentially into glia [55]. Consistently, in adult SVZ, EGFR is specifically expressed by undifferentiated precursors (the transit-amplifying cells or C-cells), which are characterized by the absence of neuronal or glial markers [51,56].…”

“…Cells isolated from the SVZ of P2 EGFR knock-out mice, show complete ablation of EGFR, loose, in vitro, symmetric stem cell division that characterized selfrenewal but also display alterations in the capability of differentiate, since wild-type neurospheres are able to produce astrocytes and neurons, while neurospheres not expressing EGFR are able only to differentiate into astrocytes ( Figure 4 A). These results demonstrate the importance of EGFR in NSCs selfrenewal and that loss of EGFR signaling in cells derived from SVZ leads them to differentiate preferentially into glia [ 55 ]. Consistently, in adult SVZ, EGFR is specifically expressed by undifferentiated precursors (the transit-amplifying cells or C-cells), which are characterized by the absence of neuronal or glial markers [ 51 , 56 ].…”

“…In order to understand if the neurodegeneration that occurs in mice lacking EGFR is due to a defect in the regulation of neural stem cells, the effect of EGFR depletion on stem cells derived from SVZ was evaluated [ 55 ]. Cells isolated from the SVZ of P2 EGFR knock-out mice, show complete ablation of EGFR, loose, in vitro, symmetric stem cell division that characterized selfrenewal but also display alterations in the capability of differentiate, since wild-type neurospheres are able to produce astrocytes and neurons, while neurospheres not expressing EGFR are able only to differentiate into astrocytes ( Figure 4 A).…”

Targeting EGFR in glioblastoma with a novel brain-penetrant small molecule EGFR-TKI

“…A recent study showed that, while EGFR is important for brain development during embryonic and early postnatal stages, adult mice with brain-specific deletion of EGFR appear to be normal (Robson et al, 2018), suggesting that EGFR inhibition in the CNS will not lead to dose-limiting toxicity. Thus, the distinct pharmacologic properties of CM93, in particular its high brain/plasma ratio, will potentially provide a "tissue-based" therapeutic window to allow effective inhibition of EGFR in the tumor, while relatively sparing the receptor systemically.…”

The FEBS Journal: hidden gems

“…Mice lacking EGFR develop postnatal neurodegeneration. To circumvent the strong developmental defects and lethality associated with EGFR knockout (KO) mice, Maria Sibilia and colleagues [3] generated two lines of conditional EGFR KO mice with an adult brain-specific ablation of EGFR. Mice lacking EGFR in the brain showed growth retardation, but no significant behavioural changes compared with control littermates.…”