FGF/EGF signaling regulates the renewal of early nephron progenitors during embryonic development.
Recent studies indicate that nephron progenitor cells of the embryonic kidney are arranged in a series of compartments of an increasing state of differentiation. The earliest progenitor compartment, distinguished by expression of CITED1, possesses greater capacity for renewal and differentiation than later compartments. Signaling events governing progression of nephron progenitor cells through stages of increasing differentiation are poorly understood, and their elucidation will provide key insights into normal and dysregulated nephrogenesis, as well as into regenerative processes that follow kidney injury. In this study, we found that the mouse CITED1(+) progenitor compartment is maintained in response to receptor tyrosine kinase (RTK) ligands that activate both FGF and EGF receptors. This RTK signaling function is dependent on RAS and PI3K signaling but not ERK. In vivo, RAS inactivation by expression of sprouty 1 (Spry1) in CITED1(+) nephron progenitors results in loss of characteristic molecular marker expression and in increased death of progenitor cells. Lineage tracing shows that surviving Spry1-expressing progenitor cells are impaired in their subsequent epithelial differentiation, infrequently contributing to epithelial structures. These findings demonstrate that the survival and developmental potential of cells in the earliest embryonic nephron progenitor cell compartment are dependent on FGF/EGF signaling through RAS.
Center for Molecular Medicine, Maine Medical Center Research Institute, 81 Research Drive, Scarborough, ME 04074, USA.
Aaron C
AC
Brown
Derek
D
Adams
Mark
M
de Caestecker
Xuehui
X
Yang
Robert
R
Friesel
Leif
L
Oxburgh
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002454:Cell Differentiation / Q000502:physiology*; D019070:Cell Lineage; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D005697:Galactosides; D020287:In Situ Nick-End Labeling; D007211:Indoles; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D009399:Nephrons / Q000166:cytology / Q000196:embryology*; D009687:Nuclear Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D016133:Polymerase Chain Reaction; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D004815:Epidermal Growth Factor; D005346:Fibroblast Growth Factors; D005697:Galactosides; D007211:Indoles; D008565:Membrane Proteins; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D020794:Receptor Protein-Tyrosine Kinases; D015534:Trans-Activators; D018631:ras Proteins; C102208:Cited1 protein, mouse; C425468:Spry1 protein, mouse; C044888:5-bromo-4-chloro-3-indolyl beta-galactoside