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First published online 26 August 2009
doi: 10.1242/dev.032979

Development 136, 3347-3356 (2009)
Published by The Company of Biologists 2009
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Mig-6 is required for appropriate lung development and to ensure normal adult lung homeostasis

Nili Jin1, Sung-Nam Cho1, M. Gabriela Raso2, Ignacio Wistuba2, Yvonne Smith3, Yanan Yang2, Jonathan M. Kurie2, Rudolph Yen2, Christopher M. Evans4, Thomas Ludwig5, Jae-Wook Jeong1 and Francesco J. DeMayo1,*

1 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
2 Department of Thoracic/Head and Neck Medical Oncology, University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
3 Institute of Immunology, NUI Maynooth, Co. Kildare, Ireland.
4 Department of Pulmonary Medicine, The University of Texas M.D Anderson Cancer Center, Houston, TX 77030, USA.
5 Institute for Cancer Genetics, Columbia University Health Science Division, Columbia University, New York, NY 10027, USA.

* Author for correspondence (fdemayo{at}bcm.edu)

Accepted 26 July 2009

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.

Key words: Mitogen-inducible gene 6 (Mig-6), Gene ablation, Lung development, EGF signaling, Vascularization


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