Mig-6 is required for appropriate lung development and to ensure normal adult lung homeostasis

Nili Jin, Sung Nam Cho, M. Gabriela Raso, Ignacio Wistuba, Yvonne Smith, Yanan Yang, Jonathan M. Kurie, Rudolph Yen, Christopher M. Evans, Thomas Ludwig, Jae Wook Jeong, Francesco J. DeMayo

Research output: Contribution to journalArticle

30 Scopus citations

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 languageEnglish (US)
Pages (from-to)3347-3356
Number of pages10
JournalDevelopment
Volume136
Issue number19
DOIs
StatePublished - 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

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    Jin, N., Cho, S. N., Raso, M. G., Wistuba, I., Smith, Y., Yang, Y., Kurie, J. M., Yen, R., Evans, C. M., Ludwig, T., Jeong, J. W., & DeMayo, F. J. (2009). Mig-6 is required for appropriate lung development and to ensure normal adult lung homeostasis. Development, 136(19), 3347-3356. https://doi.org/10.1242/dev.032979