Article abstract
Nature Genetics 40, 862 - 870 (2008)
Published online: 8 June 2008 | doi:10.1038/ng.157
A Gata6-Wnt pathway required for epithelial stem cell development and airway regeneration
Yuzhen Zhang1, Ashley M Goss2, Ethan David Cohen1, Rachel Kadzik2, John J Lepore1, Karthika Muthukumaraswamy1, Jifu Yang1, Francesco J DeMayo3, Jeffrey A Whitsett4, Michael S Parmacek1,5,6 & Edward E Morrisey1,2,5,6
Abstract
Epithelial organs, including the lung, are known to possess regenerative abilities through activation of endogenous stem cell populations, but the molecular pathways regulating stem cell expansion and regeneration are not well understood. Here we show that Gata6 regulates the temporal appearance and number of bronchioalveolar stem cells (BASCs) in the lung, its absence in Gata6-null lung epithelium leading to the precocious appearance of BASCs and concurrent loss in epithelial differentiation. This expansion of BASCs was the result of a pronounced increase in canonical Wnt signaling in lung epithelium upon loss of Gata6. Expression of the noncanonical Wnt receptor Fzd2 was downregulated in Gata6 mutants and increased Fzd2 or decreased 
-catenin expression rescued, in part, the lung epithelial defects in Gata6 mutants. During lung epithelial regeneration, canonical Wnt signaling was activated in the niche containing BASCs and forced activation of Wnt signaling led to a large increase in BASC numbers. Moreover, Gata6 was required for proper lung epithelial regeneration, and postnatal loss of Gata6 led to increased BASC expansion and decreased differentiation. Together, these data demonstrate that Gata6-regulated Wnt signaling controls the balance between progenitor expansion and epithelial differentiation required for both lung development and regeneration.
- Department of Medicine, University of Pennsylvania, 956 BRB II/III, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA.
- Department of Cell and Developmental Biology, University of Pennsylvania, 956 BRB II/III, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA.
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
- Division of Pulmonary Biology, Cincinnati's Children's Hospital and Medical Center, Cincinnati, Ohio 45229, USA.
- Institute for Regenerative Medicine, University of Pennsylvania, 956 BRB II/III, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA.
- Cardiovascular Institute, University of Pennsylvania, 956 BRB II/III, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA.
Correspondence to: Edward E Morrisey1,2,5,6 e-mail: emorrise@mail.med.upenn.edu
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