A Gata6-Wnt pathway required for epithelial stem cell development and airway regeneration.
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 beta-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.
Yuzhen
Y
Zhang
Ashley M
AM
Goss
Ethan David
ED
Cohen
Rachel
R
Kadzik
John J
JJ
Lepore
Karthika
K
Muthukumaraswamy
Jifu
J
Yang
Francesco J
FJ
DeMayo
Jeffrey A
JA
Whitsett
Michael S
MS
Parmacek
Edward E
EE
Morrisey
D000818:Animals; D049109:Cell Proliferation; D004622:Embryo, Mammalian; D004847:Epithelial Cells / Q000502:physiology; D051157:Frizzled Receptors / Q000502:physiology; D050993:GATA6 Transcription Factor / Q000235:genetics / Q000502:physiology*; D020869:Gene Expression Profiling; D008168:Lung / Q000196:embryology / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D043562:Receptors, G-Protein-Coupled / Q000502:physiology; D012038:Regeneration / Q000235:genetics* / Q000502:physiology; D020545:Respiratory Mucosa / Q000378:metabolism / Q000502:physiology*; D012143:Respiratory Physiological Phenomena; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells / Q000378:metabolism / Q000502:physiology*; D051153:Wnt Proteins / Q000502:physiology*; D051176:beta Catenin / Q000037:antagonists & inhibitors
D051157:Frizzled Receptors; C489743:Fzd2 protein, mouse; D050993:GATA6 Transcription Factor; D043562:Receptors, G-Protein-Coupled; D051153:Wnt Proteins; D051176:beta Catenin