Abstract
Mitogen-inducible gene 6 [Mig-6; Errfi1 (ErbB receptor feedback inhibitor 1); RALT (receptor-associated late transducer); gene 33] is a ubiquitously expressed adaptor protein containing CRIB, SH3 and 14-3-3 interacting domains and has been shown to negatively regulate EGF signaling. Ablation of Mig-6 results in a partial lethal phenotype in which surviving mice acquire degenerative joint diseases and tumors in multiple organs. We have determined that the early lethality in Mig-6-/- mice occurs in the perinatal period, with mice displaying abnormal lung development. Histological examination of Mig-6-/- lungs (E15.5-P3) revealed reduced septation, airway over-branching, alveolar type II cell hyperplasia, and disturbed vascular formation. In neonatal Mig-6-/- lungs, cell proliferation increased in the airway epithelium but apoptosis increased in the blood vessels. Adult Mig-6-/- mice developed features of chronic obstructive pulmonary disease (COPD); however, when Mig-6 was inducibly ablated in adult mice (Mig-6d/d), the lungs were normal. Knockdown of MIG-6 in H441 human bronchiolar epithelial cells increased phospho-EGFR and phospho-AKT levels as well as cell proliferation, whereas knockdown of MIG-6 in human lung microvascular endothelial (HMVEC-L) cells promoted their apoptosis. These results demonstrate that Mig-6 is required for prenatal and perinatal lung development, in part through the regulation of EGF signaling, as well as for maintaining proper pulmonary vascularization.
Original language | English (US) |
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Pages (from-to) | 3347-3356 |
Number of pages | 10 |
Journal | Development |
Volume | 136 |
Issue number | 19 |
DOIs | |
State | Published - Oct 1 2009 |
Keywords
- EGF signaling
- Gene ablation
- Lung development
- Mitogen-inducible gene 6 (Mig-6)
- Vascularization
ASJC Scopus subject areas
- Molecular Biology
- Developmental Biology