Bmp7 Maintains Undifferentiated Kidney Progenitor Population and Determines Nephron Numbers at Birth

The number of nephrons, the functional units of the kidney, varies among individuals. A low nephron number at birth is associated with a risk of hypertension and the progression of renal insufficiency. The molecular mechanisms determining nephron number during embryogenesis have not yet been clarifi...

Descripción completa

Detalles Bibliográficos
Autores principales: Tomita, Mayumi, Asada, Misako, Asada, Nariaki, Nakamura, Jin, Oguchi, Akiko, Higashi, Atsuko Y., Endo, Shuichiro, Robertson, Elizabeth, Kimura, Takeshi, Kita, Toru, Economides, Aris N., Kreidberg, Jordan, Yanagita, Motoko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753328/
https://www.ncbi.nlm.nih.gov/pubmed/23991197
http://dx.doi.org/10.1371/journal.pone.0073554
_version_ 1782281816039751680
author Tomita, Mayumi
Asada, Misako
Asada, Nariaki
Nakamura, Jin
Oguchi, Akiko
Higashi, Atsuko Y.
Endo, Shuichiro
Robertson, Elizabeth
Kimura, Takeshi
Kita, Toru
Economides, Aris N.
Kreidberg, Jordan
Yanagita, Motoko
author_facet Tomita, Mayumi
Asada, Misako
Asada, Nariaki
Nakamura, Jin
Oguchi, Akiko
Higashi, Atsuko Y.
Endo, Shuichiro
Robertson, Elizabeth
Kimura, Takeshi
Kita, Toru
Economides, Aris N.
Kreidberg, Jordan
Yanagita, Motoko
author_sort Tomita, Mayumi
collection PubMed
description The number of nephrons, the functional units of the kidney, varies among individuals. A low nephron number at birth is associated with a risk of hypertension and the progression of renal insufficiency. The molecular mechanisms determining nephron number during embryogenesis have not yet been clarified. Germline knockout of bone morphogenetic protein 7 (Bmp7) results in massive apoptosis of the kidney progenitor cells and defects in early stages of nephrogenesis. This phenotype has precluded analysis of Bmp7 function in the later stage of nephrogenesis. In this study, utilization of conditional null allele of Bmp7 in combination with systemic inducible Cre deleter mice enabled us to analyze Bmp7 function at desired time points during kidney development, and to discover the novel function of Bmp7 to inhibit the precocious differentiation of the progenitor cells to nephron. Systemic knockout of Bmp7 in vivo after the initiation of kidney development results in the precocious differentiation of the kidney progenitor cells to nephron, in addition to the prominent apoptosis of progenitor cells. We also confirmed that in vitro knockout of Bmp7 in kidney explant culture results in the accelerated differentiation of progenitor population. Finally we utilized colony-forming assays and demonstrated that Bmp7 inhibits epithelialization and differentiation of the kidney progenitor cells. These results indicate that the function of Bmp7 to inhibit the precocious differentiation of the progenitor cells together with its anti-apoptotic effect on progenitor cells coordinately maintains renal progenitor pool in undifferentiated status, and determines the nephron number at birth.
format Online
Article
Text
id pubmed-3753328
institution National Center for Biotechnology Information
language English
publishDate 2013
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-37533282013-08-29 Bmp7 Maintains Undifferentiated Kidney Progenitor Population and Determines Nephron Numbers at Birth Tomita, Mayumi Asada, Misako Asada, Nariaki Nakamura, Jin Oguchi, Akiko Higashi, Atsuko Y. Endo, Shuichiro Robertson, Elizabeth Kimura, Takeshi Kita, Toru Economides, Aris N. Kreidberg, Jordan Yanagita, Motoko PLoS One Research Article The number of nephrons, the functional units of the kidney, varies among individuals. A low nephron number at birth is associated with a risk of hypertension and the progression of renal insufficiency. The molecular mechanisms determining nephron number during embryogenesis have not yet been clarified. Germline knockout of bone morphogenetic protein 7 (Bmp7) results in massive apoptosis of the kidney progenitor cells and defects in early stages of nephrogenesis. This phenotype has precluded analysis of Bmp7 function in the later stage of nephrogenesis. In this study, utilization of conditional null allele of Bmp7 in combination with systemic inducible Cre deleter mice enabled us to analyze Bmp7 function at desired time points during kidney development, and to discover the novel function of Bmp7 to inhibit the precocious differentiation of the progenitor cells to nephron. Systemic knockout of Bmp7 in vivo after the initiation of kidney development results in the precocious differentiation of the kidney progenitor cells to nephron, in addition to the prominent apoptosis of progenitor cells. We also confirmed that in vitro knockout of Bmp7 in kidney explant culture results in the accelerated differentiation of progenitor population. Finally we utilized colony-forming assays and demonstrated that Bmp7 inhibits epithelialization and differentiation of the kidney progenitor cells. These results indicate that the function of Bmp7 to inhibit the precocious differentiation of the progenitor cells together with its anti-apoptotic effect on progenitor cells coordinately maintains renal progenitor pool in undifferentiated status, and determines the nephron number at birth. Public Library of Science 2013-08-26 /pmc/articles/PMC3753328/ /pubmed/23991197 http://dx.doi.org/10.1371/journal.pone.0073554 Text en © 2013 Tomita et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Tomita, Mayumi
Asada, Misako
Asada, Nariaki
Nakamura, Jin
Oguchi, Akiko
Higashi, Atsuko Y.
Endo, Shuichiro
Robertson, Elizabeth
Kimura, Takeshi
Kita, Toru
Economides, Aris N.
Kreidberg, Jordan
Yanagita, Motoko
Bmp7 Maintains Undifferentiated Kidney Progenitor Population and Determines Nephron Numbers at Birth
title Bmp7 Maintains Undifferentiated Kidney Progenitor Population and Determines Nephron Numbers at Birth
title_full Bmp7 Maintains Undifferentiated Kidney Progenitor Population and Determines Nephron Numbers at Birth
title_fullStr Bmp7 Maintains Undifferentiated Kidney Progenitor Population and Determines Nephron Numbers at Birth
title_full_unstemmed Bmp7 Maintains Undifferentiated Kidney Progenitor Population and Determines Nephron Numbers at Birth
title_short Bmp7 Maintains Undifferentiated Kidney Progenitor Population and Determines Nephron Numbers at Birth
title_sort bmp7 maintains undifferentiated kidney progenitor population and determines nephron numbers at birth
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753328/
https://www.ncbi.nlm.nih.gov/pubmed/23991197
http://dx.doi.org/10.1371/journal.pone.0073554
work_keys_str_mv AT tomitamayumi bmp7maintainsundifferentiatedkidneyprogenitorpopulationanddeterminesnephronnumbersatbirth
AT asadamisako bmp7maintainsundifferentiatedkidneyprogenitorpopulationanddeterminesnephronnumbersatbirth
AT asadanariaki bmp7maintainsundifferentiatedkidneyprogenitorpopulationanddeterminesnephronnumbersatbirth
AT nakamurajin bmp7maintainsundifferentiatedkidneyprogenitorpopulationanddeterminesnephronnumbersatbirth
AT oguchiakiko bmp7maintainsundifferentiatedkidneyprogenitorpopulationanddeterminesnephronnumbersatbirth
AT higashiatsukoy bmp7maintainsundifferentiatedkidneyprogenitorpopulationanddeterminesnephronnumbersatbirth
AT endoshuichiro bmp7maintainsundifferentiatedkidneyprogenitorpopulationanddeterminesnephronnumbersatbirth
AT robertsonelizabeth bmp7maintainsundifferentiatedkidneyprogenitorpopulationanddeterminesnephronnumbersatbirth
AT kimuratakeshi bmp7maintainsundifferentiatedkidneyprogenitorpopulationanddeterminesnephronnumbersatbirth
AT kitatoru bmp7maintainsundifferentiatedkidneyprogenitorpopulationanddeterminesnephronnumbersatbirth
AT economidesarisn bmp7maintainsundifferentiatedkidneyprogenitorpopulationanddeterminesnephronnumbersatbirth
AT kreidbergjordan bmp7maintainsundifferentiatedkidneyprogenitorpopulationanddeterminesnephronnumbersatbirth
AT yanagitamotoko bmp7maintainsundifferentiatedkidneyprogenitorpopulationanddeterminesnephronnumbersatbirth