The EGF receptor is required for efficient liver regeneration

Abstract

Mice lacking the EGF receptor (EGFR) die between midgestation and postnatal day 20 with various defects in neural and epithelial organs. Here, we generated mice carrying a floxed EGFR allele to inactivate the EGFR in fetal and adult liver. Perinatal deletion of EGFR in hepatocytes resulted in decreased body weight, whereas deletion in the adult liver did not affect body mass. Although liver function was not affected, after partial hepatectomy mice lacking EGFR in the liver showed increased mortality accompanied by increased levels of serum transaminases indicating liver damage. Liver regeneration was delayed in the mutants because of reduced hepatocyte proliferation. Analysis of cell cycle progression in EGFR-deficient livers indicated a defective G 1 –S phase entry with delayed transcriptional activation and reduced protein expression of cyclin D1 followed by reduced cdk2 and cdk1 expression. Impaired liver regeneration was accompanied by compensatory up-regulation of TNFα in the serum and prolonged activation of c-Jun. Moreover, p38α and NF-κB activation was reduced in regenerating mutant livers, indicating an impaired stress response after hepatectomy. Our studies demonstrate that EGFR is a critical regulator of hepatocyte proliferation in the initial phases of liver regeneration.

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

“…To better investigate the role of EGFR in adult brain development we bred mice with a conditional EGFR allele (floxed EGFR allele; EGFR f ) 31 with two brain‐specific Cre lines with slightly different temporal and spatial expression profiles. Cre recombinase expression from the rat nestin promoter 25 was used to induce recombination of the EGFR f allele in all cells of the central nervous system (EGFR ΔNes ), beginning from approximately E14.5.…”

Activation of the Transcription Factor GLI1 by WNT Signaling Underlies the Role of SULFATASE 2 as a Regulator of Tissue Regeneration

“…In this study, we used liver after partial hepatectomy (PH) as a model of tissue regeneration. This model has been extensively characterized at the biological level, and the kinetics of cell proliferation, and activation of ligands and pathways involved in the process of liver regeneration post-hepatectomy are well known (1)(2)(3)(4)16). However, the molecular mechanisms regulating the interplay between these ligand-activated pathways and the downstream effectors remain elusive.…”

“…Release from extracellular storage is one of the most frequent mechanisms modulating the activity of these ligands (5). The SULFATASE 2 (SULF2) 4 is a heparan sulfate (HS) endosulfatase enzyme that removes 6-O-sulfate moieties from disaccharide units in HS proteoglycans (HSPGs) (6,7). HSPGs are present on the cell surface and in the extracellular matrix of virtually all animal cells and act both as storage or sequestration sites for growth factors and as co-receptors in growth factor-receptor interactions (5).…”

“…Regulation of tissue regeneration involves the ligand-dependent activation of multiple growth factor pathways (1)(2)(3)(4). Release from extracellular storage is one of the most frequent mechanisms modulating the activity of these ligands (5).…”

EGFR is dispensable for c-Met-mediated proliferation and survival activities in mouse adult liver oval cells

“…In this study we have directly approached the relevance of EGFR- It is well known that the EGFR and its ligands play a critical role in the proliferative response accompanying liver regeneration after partial hepatectomy [23]. In fact, mice lacking EGFR showed a delay in liver regeneration due to a reduced hepatocyte proliferation and cell cycle progression [31]. In contrast, scarce data is available in the literature regarding EGFR signalling in progenitormediated liver regeneration.…”