NADPH oxidase 1 modulates WNT and NOTCH1 signaling to control the fate of proliferative progenitor cells in the colon.
The homeostatic self-renewal of the colonic epithelium requires coordinated regulation of the canonical Wnt/beta-catenin and Notch signaling pathways to control proliferation and lineage commitment of multipotent stem cells. However, the molecular mechanisms by which the Wnt/beta-catenin and Notch1 pathways interplay in controlling cell proliferation and fate in the colon are poorly understood. Here we show that NADPH oxidase 1 (NOX1), a reactive oxygen species (ROS)-producing oxidase that is highly expressed in colonic epithelial cells, is a pivotal determinant of cell proliferation and fate that integrates Wnt/beta-catenin and Notch1 signals. NOX1-deficient mice reveal a massive conversion of progenitor cells into postmitotic goblet cells at the cost of colonocytes due to the concerted repression of phosphatidylinositol 3-kinase (PI3K)/AKT/Wnt/beta-catenin and Notch1 signaling. This conversion correlates with the following: (i) the redox-dependent activation of the dual phosphatase PTEN, causing the inactivation of the Wnt pathway effector beta-catenin, and (ii) the downregulation of Notch1 signaling that provokes derepression of mouse atonal homolog 1 (Math1) expression. We conclude that NOX1 controls the balance between goblet and absorptive cell types in the colon by coordinately modulating PI3K/AKT/Wnt/beta-catenin and Notch1 signaling. This finding provides the molecular basis for the role of NOX1 in cell proliferation and postmitotic differentiation.
Coant
Nicolas
N
INSERM, U773, Centre de Recherche Bichat Beaujon, CRB3, BP 416, 16 rue Henri Huchard, Paris 75018, France.
Ben Mkaddem
Sanae
S
Pedruzzi
Eric
E
Guichard
Cécile
C
Tréton
Xavier
X
Ducroc
Robert
R
Freund
Jean-Noel
JN
Cazals-Hatem
Dominique
D
Bouhnik
Yoram
Y
Woerther
Paul-Louis
PL
Skurnik
David
D
Grodet
Alain
A
Fay
Michèle
M
Biard
Denis
D
Lesuffleur
Thécla
T
Deffert
Christine
C
Moreau
Richard
R
Groyer
André
A
Krause
Karl-Heinz
KH
Daniel
Fanny
F
Ogier-Denis
Eric
E
D000818:Animals; D018938:Caco-2 Cells; D015820:Cadherins / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D019070:Cell Lineage; D049109:Cell Proliferation; D003106:Colon / Q000166:cytology* / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D039902:Multipotent Stem Cells / Q000166:cytology / Q000502:physiology*; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000074624:NADPH Oxidase 1; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
D015820:Cadherins; D017382:Reactive Oxygen Species; D051881:Receptor, Notch1; D051153:Wnt Proteins; D051176:beta Catenin; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; C000614711:NOX1 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase