Omics profiling identifies the regulatory functions of the MAPK/ERK pathway in nephron progenitor metabolism
| العنوان: | Omics profiling identifies the regulatory functions of the MAPK/ERK pathway in nephron progenitor metabolism |
|---|---|
| المؤلفون: | Hyuk Nam Kwon, Kristen Kurtzeborn, Vladislav Iaroshenko, Xing Jin, Abigail Loh, Nathalie Escande-Beillard, Bruno Reversade, Sunghyouk Park, Satu Kuure |
| المساهمون: | Veterinary Biosciences, Mitochondrial Morphogenesis, Kidney development, Helsinki Institute of Life Science HiLIFE, STEMM - Stem Cells and Metabolism Research Program, Helsinki Institute of Life Science HiLIFE, Infra, Biosciences, Reversade, Bruno, Kwon, H.N., Kurtzeborn, K., Laroshenko, V., Jin, X., Loh, A., Escande-Beillard, N., Park, S., Kuure, S., School of Medicine |
| المصدر: | Development |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | Proline, MAP Kinase Signaling System, Stem Cells, Organogenesis, Cell Differentiation, Nephrons, Tissue-specific progenitors, Development, Kidney, Pycr1/Pycr2, Differentiation, Intracellular signaling cascades, Metabolism, Receptor tyrosine kinase signaling, Self-renewal, Mice, Developmental biology, Animals, 1182 Biochemistry, cell and molecular biology, Amino Acids, Oxidoreductases, Pyruvates, Molecular Biology, Developmental Biology |
| الوصف: | Nephron endowment is defined by fetal kidney growth and crucially dictates renal health in adults. Defects in the molecular regulation of nephron progenitors contribute to only a fraction of reduced nephron mass cases, suggesting alternative causative mechanisms. The importance of MAPK/ERK activation in nephron progenitor maintenance has been previously demonstrated, and here, we characterized the metabolic consequences of MAPK/ERK deficiency. Liquid chromatography/mass spectrometry-based metabolomics profiling identified 42 reduced metabolites, of which 26 were supported by in vivo transcriptional changes in MAPK/ERK-deficient nephron progenitors. Among these, mitochondria, ribosome and amino acid metabolism, together with diminished pyruvate and proline metabolism, were the most affected pathways. In vitro cultures of mouse kidneys demonstrated a dosage-specific function for pyruvate in controlling the shape of the ureteric bud tip, a regulatory niche for nephron progenitors. In vivo disruption of proline metabolism caused premature nephron progenitor exhaustion through their accelerated differentiation in pyrroline-5-carboxylate reductases 1 (Pycr1) and 2 (Pycr2) double-knockout kidneys. Pycr1/Pycr2-deficient progenitors showed normal cell survival, indicating no changes in cellular stress. Our results suggest that MAPK/ERK-dependent metabolism functionally participates in nephron progenitor maintenance by monitoring pyruvate and proline biogenesis in developing kidneys. This work was supported by funds from the Academy of Finland (309997 to S.K.), the Finnish Cultural Foundation (Suomen Kulttuurirahasto; to S.K. and H.N.K.), the Maud Kuistila Foundation (Maud Kuistilan Muistosa?a?tio?; to S.K. and K.K.), Pediatric Cancer Foundation Va?re (Lasten Syo?pa?sa?a?tio? Va?reen; to S.K.), Aamu Pediatric Cancer Foundation (S.K.) and the Orion Research Foundation (Orionin Tutkimussa?a?tio?; K.K.). Open Access funding provided by the Aamu Pediatric Cancer Foundation. Deposited in PMC for immediate release. |
| وصف الملف: | |
| اللغة: | English |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e99ca7d4d51f452f2e53eaea760b9ddc http://hdl.handle.net/10138/355227 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....e99ca7d4d51f452f2e53eaea760b9ddc |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |