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

Abstract

Stimulation of the epidermal growth factor receptor (EGF-R) produces numerous effects on central nervous system (CNS) cells in vitro including neuronal survival and differentiation, astrocyte proliferation and the proliferation of multipotent progenitors. However, the in vivo role of EGF-R is less well understood. In the present study, we demonstrate that EGF-R null mice generated on a 129Sv/J Swiss Black background undergo focal but massive degeneration the olfactory bulb, piriform cortex, neocortex, and thalamus between postnatal days 5 and 8 which is due, at least in part, to apoptosis. Some of the neuronal populations that degenerate do not normally express EGF-R, indicating an indirect mechanism of neuronal death. There were also delays in GFAP expression within the glia limitans and within structures outside the germinal zones in early postnatal ages. At or just prior to the onset of the degeneration, however, there was an increase in GFAP expression in these areas. The brains of EGF-R (-/-) animals were smaller but cytoarchitecturally normal at birth and neuronal populations appeared to be intact, including striatal GABAergic and midbrain dopaminergic neurons which have previously been shown to express EGF-R. Multipotent progenitors and astrocytes derived from EGF-R (-/-) mice were capable of proliferating in response to FGF-2. These data demonstrate that EGF-R expression is critical for the maintenance of large portions of the postnatal mouse forebrain as well as the normal development of astrocytes.

The epidermal growth factor receptor family: Biology driving targeted therapeutics

“…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].…”

Neuronal stem cells in the central nervous system and in human diseases

“…The activation of EGFR triggers classic PI3K-Akt or Ras-MAPK signals, thus regulating cell proliferation and migration (Wells et al, 2002). EGFR activation promotes cell growth of astrocyte precursors and neural stem cells (Reynolds et al, 1992;Seidman et al, 1997;Kornblum et al, 1998). In high-grade astrocytomas, the most common type of glioma, approximately 50% of cases exhibit EGFR amplification, and this activation appears critical in the transformation process (Maher et al, 2001;Wechsler-Reya and Scott, 2001).…”

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

“…Because TGFα has mitotic actions on putative progenitor cells (Kornblum et al, 1998(Kornblum et al, , 1999Reynolds and Weiss, 1992), chronic treatment for more than 5 days with TGFα markedly enhanced proliferation of these non-neuronal cells in neocortical cultures. To minimize the indirect effects of TGFα via proliferating non-neuronal cells, cultures were treated with AraC for 48 h from 4 DIV.…”

“…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.…”