Postnatal prolongation of mammalian nephrogenesis by excess fetal GDNF.

Autor:	Li H; Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland.; Helsinki Institute of Life Science, University of Helsinki, 00014 Helsinki, Finland., Kurtzeborn K; Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland.; Helsinki Institute of Life Science, University of Helsinki, 00014 Helsinki, Finland., Kupari J; Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland., Gui Y; Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland., Siefker E; Department of Developmental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68105, USA., Lu B; Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA., Mätlik K; Helsinki Institute of Life Science, University of Helsinki, 00014 Helsinki, Finland.; Department of Pharmacology, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland., Olfat S; Helsinki Institute of Life Science, University of Helsinki, 00014 Helsinki, Finland.; Department of Pharmacology, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland., Montaño-Rodríguez AR; Helsinki Institute of Life Science, University of Helsinki, 00014 Helsinki, Finland.; Department of Pharmacology, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland., Huh SH; Department of Developmental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68105, USA., Costantini F; Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA., Andressoo JO; Helsinki Institute of Life Science, University of Helsinki, 00014 Helsinki, Finland.; Department of Pharmacology, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland.; Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 171 77 Stockholm, Sweden., Kuure S; Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland.; GM-unit, Laboratory Animal Centre, Helsinki Institute of Life Science, University of Helsinki, 00014 Helsinki, Finland.
Jazyk:	angličtina
Zdroj:	Development (Cambridge, England) [Development] 2021 May 15; Vol. 148 (10). Date of Electronic Publication: 2021 May 25.
DOI:	10.1242/dev.197475
Abstrakt:	Nephron endowment, defined during the fetal period, dictates renal and related cardiovascular health throughout life. We show here that, despite its negative effects on kidney growth, genetic increase of GDNF prolongs the nephrogenic program beyond its normal cessation. Multi-stage mechanistic analysis revealed that excess GDNF maintains nephron progenitors and nephrogenesis through increased expression of its secreted targets and augmented WNT signaling, leading to a two-part effect on nephron progenitor maintenance. Abnormally high GDNF in embryonic kidneys upregulates its known targets but also Wnt9b and Axin2, with concomitant deceleration of nephron progenitor proliferation. Decline of GDNF levels in postnatal kidneys normalizes the ureteric bud and creates a permissive environment for continuation of the nephrogenic program, as demonstrated by morphologically and molecularly normal postnatal nephron progenitor self-renewal and differentiation. These results establish that excess GDNF has a bi-phasic effect on nephron progenitors in mice, which can faithfully respond to GDNF dosage manipulation during the fetal and postnatal period. Our results suggest that sensing the signaling activity level is an important mechanism through which GDNF and other molecules contribute to nephron progenitor lifespan specification. Competing Interests: Competing interests The authors declare no competing or financial interests. (© 2021. Published by The Company of Biologists Ltd.)
Databáze:	MEDLINE
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