Omics profiling identifies the regulatory functions of the MAPK/ERK pathway in nephron progenitor metabolism.
Pycr1/Pycr2
Development
Differentiation
Intracellular signaling cascades
Metabolism
Organogenesis
Receptor tyrosine kinase signaling
Self-renewal
Tissue-specific progenitors
Journal
Development (Cambridge, England)
ISSN: 1477-9129
Titre abrégé: Development
Pays: England
ID NLM: 8701744
Informations de publication
Date de publication:
01 10 2022
01 10 2022
Historique:
received:
25
05
2022
accepted:
25
08
2022
entrez:
3
10
2022
pubmed:
4
10
2022
medline:
5
10
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 36189831
pii: 276992
doi: 10.1242/dev.200986
pmc: PMC9641663
pii:
doi:
Substances chimiques
Amino Acids
0
Pyruvates
0
Proline
9DLQ4CIU6V
Oxidoreductases
EC 1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2022. Published by The Company of Biologists Ltd.
Déclaration de conflit d'intérêts
Competing interests The authors declare no competing or financial interests.
Références
Clin Pharmacol Ther. 2019 Sep;106(3):544-556
pubmed: 31173340
Cell Metab. 2015 Mar 3;21(3):392-402
pubmed: 25738455
Proc Natl Acad Sci U S A. 2018 Jun 5;115(23):5998-6003
pubmed: 29784808
Diabetes Care. 2011 Dec;34(12):2624-30
pubmed: 22110171
EMBO Rep. 2016 Dec;17(12):1776-1784
pubmed: 27827794
J Inherit Metab Dis. 2017 Jul;40(4):609-620
pubmed: 28653176
Pediatr Nephrol. 2011 Sep;26(9):1529-33
pubmed: 21604189
Anal Chem. 2018 Mar 6;90(5):3156-3164
pubmed: 29381867
Int J Mol Sci. 2019 Apr 10;20(7):
pubmed: 30974877
J Am Soc Nephrol. 2021 Aug;32(8):1898-1912
pubmed: 33958489
Science. 2002 Mar 1;295(5560):1662-4
pubmed: 11872829
Dev Biol. 2011 Dec 1;360(1):110-22
pubmed: 21963425
Kidney Int. 2018 Aug;94(2):259-267
pubmed: 29685496
Bioinformatics. 2009 Apr 15;25(8):1091-3
pubmed: 19237447
Methods Mol Biol. 2019;1926:23-30
pubmed: 30742259
Commun Biol. 2021 May 17;4(1):589
pubmed: 34002016
EMBO J. 2006 Nov 1;25(21):5214-28
pubmed: 17036046
Clin Chem. 2006 Jul;52(7):1406-14
pubmed: 16690733
Nat Genet. 2009 Sep;41(9):1016-21
pubmed: 19648921
J Cent Nerv Syst Dis. 2021 Jan 31;13:1179573520988193
pubmed: 33597815
Proc Natl Acad Sci U S A. 2013 Mar 19;110(12):4640-5
pubmed: 23487745
Nature. 2016 Mar 24;531(7595):528-32
pubmed: 26982719
Lab Invest. 1991 Jun;64(6):777-84
pubmed: 2046329
Cell Death Differ. 2014 Nov;21(11):1696-708
pubmed: 24926615
Nephrol Dial Transplant. 2014 Aug;29(8):1467-74
pubmed: 24366899
Annu Rev Plant Biol. 2003;54:669-89
pubmed: 14503007
Stem Cell Reports. 2021 Feb 9;16(2):354-369
pubmed: 33482102
J Mol Cell Biol. 2011 Apr;3(2):108-22
pubmed: 21307025
Genetics. 2021 May 17;218(1):
pubmed: 33734376
Nat Genet. 2000 May;25(1):25-9
pubmed: 10802651
Mol Cell Biol. 2003 Jul;23(14):4778-87
pubmed: 12832465
Development. 2001 Nov;128(21):4329-38
pubmed: 11684667
Am J Physiol Cell Physiol. 2010 May;298(5):C982-92
pubmed: 20164384
J Cell Sci. 2021 May 1;134(9):
pubmed: 33973637
Dev Biol. 2007 Oct 15;310(2):379-87
pubmed: 17826763
Nucleic Acids Res. 2010 Jul;38(Web Server issue):W71-7
pubmed: 20457745
Protein Sci. 2010 Nov;19(11):2031-44
pubmed: 20857498
PLoS One. 2012;7(9):e45190
pubmed: 23024808
Mol Cell. 2014 Nov 6;56(3):414-424
pubmed: 25458842
Bioinformatics. 2009 Dec 1;25(23):3151-7
pubmed: 19783829
Oncotarget. 2016 Jul 26;7(30):47954-47965
pubmed: 27323830
J Am Soc Nephrol. 2017 Nov;28(11):3323-3335
pubmed: 28754792
Bull World Health Organ. 2018 Jun 1;96(6):414-422D
pubmed: 29904224
Sci Rep. 2016 Jan 06;6:18846
pubmed: 26733354
Nucleic Acids Res. 2018 Jan 4;46(D1):D608-D617
pubmed: 29140435
Genes (Basel). 2021 Feb 23;12(2):
pubmed: 33672414
Cell Signal. 2014 Nov;26(11):2397-405
pubmed: 25041845
Biol Reprod. 2019 Apr 1;100(4):1073-1081
pubmed: 30418498
Genome Res. 2003 Nov;13(11):2498-504
pubmed: 14597658
J Reprod Fertil. 1993 Sep;99(1):87-95
pubmed: 8283458
Nat Genet. 2003 Aug;34(4):440-5
pubmed: 12858174
PLoS Genet. 2014 Mar 06;10(3):e1004193
pubmed: 24603431
Dev Cell. 2007 Apr;12(4):615-29
pubmed: 17419998
J Nutr. 1985 Apr;115(4):509-15
pubmed: 2858518
Clin J Am Soc Nephrol. 2020 May 7;15(5):723-731
pubmed: 32188635
Genes Dev. 2017 Feb 15;31(4):336-346
pubmed: 28314766
Stem Cell Reports. 2015 Apr 14;4(4):551-60
pubmed: 25754203
Dev Cell. 2010 May 18;18(5):698-712
pubmed: 20493806
iScience. 2021 Jan 26;24(2):102090
pubmed: 33615198
Stem Cell Reports. 2018 Oct 9;11(4):912-928
pubmed: 30220628
Circulation. 2020 Apr 14;141(15):1249-1265
pubmed: 32078387
Dev Cell. 2017 May 22;41(4):349-365.e3
pubmed: 28535371
Cell Metab. 2020 Oct 6;32(4):629-642.e8
pubmed: 32905798
Semin Cell Dev Biol. 2019 Jul;91:86-93
pubmed: 30172050
Annu Rev Cell Dev Biol. 2018 Oct 6;34:427-450
pubmed: 30125139
Pediatr Nephrol. 2020 Jan;35(1):1-8
pubmed: 30554363
Nat Cell Biol. 2012 Dec;14(12):1295-304
pubmed: 23178880
Nucleic Acids Res. 1999 Jan 1;27(1):29-34
pubmed: 9847135
Semin Cell Dev Biol. 2019 Jul;91:94-103
pubmed: 30030141
Kidney Int. 2002 Apr;61(4):1252-62
pubmed: 11918731
Front Cell Dev Biol. 2021 Aug 12;9:728576
pubmed: 34458276
Pediatr Nephrol. 2021 Aug;36(8):2155-2164
pubmed: 33089379
J Am Soc Nephrol. 2010 Jun;21(6):898-910
pubmed: 20150537
Cell Stem Cell. 2008 Aug 7;3(2):169-81
pubmed: 18682239
EBioMedicine. 2018 Jan;27:275-283
pubmed: 29329932
J Am Soc Nephrol. 2019 Jul;30(7):1192-1205
pubmed: 31142573
Cell Death Differ. 2011 May;18(5):769-82
pubmed: 21113145
Plant Mol Biol. 2002 Jan;48(1-2):155-71
pubmed: 11860207
Nat Commun. 2015 Jun 10;6:7209
pubmed: 26059097
Dev Cell. 2019 Mar 25;48(6):780-792.e4
pubmed: 30853441
Proc Natl Acad Sci U S A. 2007 Aug 28;104(35):14074-9
pubmed: 17709754
Stem Cell Reports. 2017 Jan 10;8(1):1-10
pubmed: 28017658
BMC Biol. 2022 May 13;20(1):112
pubmed: 35550069
Nature. 2019 Jan;565(7737):96-100
pubmed: 30487609
Neuron. 2020 Jul 8;107(1):82-94.e6
pubmed: 32330411
Development. 2011 Apr;138(7):1247-57
pubmed: 21350016
Dev Cell. 2015 Jul 27;34(2):229-41
pubmed: 26190145
Biol Reprod. 1998 Apr;58(4):1054-6
pubmed: 9546739
Development. 2015 Apr 1;142(7):1228-41
pubmed: 25804735
Development. 2014 Aug;141(15):3093-101
pubmed: 25053437
Pediatr Nephrol. 2005 Mar;20(3):432-40
pubmed: 15723268
Cell Cycle. 2012 Dec 15;11(24):4517-23
pubmed: 23165208
J Am Soc Nephrol. 2013 Nov;24(11):1901-12
pubmed: 23949796
Cell Stem Cell. 2016 Oct 6;19(4):516-529
pubmed: 27570066
Biochim Biophys Acta. 2006 Dec;1763(12):1755-66
pubmed: 17034877
Am J Physiol Heart Circ Physiol. 2012 Oct 15;303(8):H979-88
pubmed: 22904158
Development. 2021 May 15;148(10):
pubmed: 34032268
Clin Kidney J. 2018 Dec 01;12(3):382-399
pubmed: 31198539