Journal
DEVELOPMENT
Volume 138, Issue 23, Pages 5099-5112Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/dev.065995
Keywords
Nephrogenic mesenchyme; Cap mesenchyme; GUDMAP; Sprouty; EGF; FGF; TGF alpha; Mouse
Categories
Funding
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [R01DK078161, R01DK073781]
- American Heart Association
- Transgenics and Gene Targeting [2P20RR15555]
- MMCRI [2P20RR18789]
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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.
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