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An Integrated Gene Regulatory Network Controls Stem Cell Proliferation in Teeth

Epithelial stem cells reside in specific niches that regulate their self-renewal and differentiation, and are responsible for the continuous regeneration of tissues such as hair, skin, and gut. Although the regenerative potential of mammalian teeth is limited, mouse incisors grow continuously throug...

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Autores principales: Wang, Xiu-Ping, Suomalainen, Marika, Felszeghy, Szabolcs, Zelarayan, Laura C, Alonso, Maria T, Plikus, Maksim V, Maas, Richard L, Chuong, Cheng-Ming, Schimmang, Thomas, Thesleff, Irma
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2007
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1885832/
https://www.ncbi.nlm.nih.gov/pubmed/17564495
http://dx.doi.org/10.1371/journal.pbio.0050159
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author Wang, Xiu-Ping
Suomalainen, Marika
Felszeghy, Szabolcs
Zelarayan, Laura C
Alonso, Maria T
Plikus, Maksim V
Maas, Richard L
Chuong, Cheng-Ming
Schimmang, Thomas
Thesleff, Irma
author_facet Wang, Xiu-Ping
Suomalainen, Marika
Felszeghy, Szabolcs
Zelarayan, Laura C
Alonso, Maria T
Plikus, Maksim V
Maas, Richard L
Chuong, Cheng-Ming
Schimmang, Thomas
Thesleff, Irma
author_sort Wang, Xiu-Ping
collection PubMed
description Epithelial stem cells reside in specific niches that regulate their self-renewal and differentiation, and are responsible for the continuous regeneration of tissues such as hair, skin, and gut. Although the regenerative potential of mammalian teeth is limited, mouse incisors grow continuously throughout life and contain stem cells at their proximal ends in the cervical loops. In the labial cervical loop, the epithelial stem cells proliferate and migrate along the labial surface, differentiating into enamel-forming ameloblasts. In contrast, the lingual cervical loop contains fewer proliferating stem cells, and the lingual incisor surface lacks ameloblasts and enamel. Here we have used a combination of mouse mutant analyses, organ culture experiments, and expression studies to identify the key signaling molecules that regulate stem cell proliferation in the rodent incisor stem cell niche, and to elucidate their role in the generation of the intrinsic asymmetry of the incisors. We show that epithelial stem cell proliferation in the cervical loops is controlled by an integrated gene regulatory network consisting of Activin, bone morphogenetic protein (BMP), fibroblast growth factor (FGF), and Follistatin within the incisor stem cell niche. Mesenchymal FGF3 stimulates epithelial stem cell proliferation, and BMP4 represses Fgf3 expression. In turn, Activin, which is strongly expressed in labial mesenchyme, inhibits the repressive effect of BMP4 and restricts Fgf3 expression to labial dental mesenchyme, resulting in increased stem cell proliferation and a large, labial stem cell niche. Follistatin limits the number of lingual stem cells, further contributing to the characteristic asymmetry of mouse incisors, and on the basis of our findings, we suggest a model in which Follistatin antagonizes the activity of Activin. These results show how the spatially restricted and balanced effects of specific components of a signaling network can regulate stem cell proliferation in the niche and account for asymmetric organogenesis. Subtle variations in this or related regulatory networks may explain the different regenerative capacities of various organs and animal species.
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spelling pubmed-18858322007-06-12 An Integrated Gene Regulatory Network Controls Stem Cell Proliferation in Teeth Wang, Xiu-Ping Suomalainen, Marika Felszeghy, Szabolcs Zelarayan, Laura C Alonso, Maria T Plikus, Maksim V Maas, Richard L Chuong, Cheng-Ming Schimmang, Thomas Thesleff, Irma PLoS Biol Research Article Epithelial stem cells reside in specific niches that regulate their self-renewal and differentiation, and are responsible for the continuous regeneration of tissues such as hair, skin, and gut. Although the regenerative potential of mammalian teeth is limited, mouse incisors grow continuously throughout life and contain stem cells at their proximal ends in the cervical loops. In the labial cervical loop, the epithelial stem cells proliferate and migrate along the labial surface, differentiating into enamel-forming ameloblasts. In contrast, the lingual cervical loop contains fewer proliferating stem cells, and the lingual incisor surface lacks ameloblasts and enamel. Here we have used a combination of mouse mutant analyses, organ culture experiments, and expression studies to identify the key signaling molecules that regulate stem cell proliferation in the rodent incisor stem cell niche, and to elucidate their role in the generation of the intrinsic asymmetry of the incisors. We show that epithelial stem cell proliferation in the cervical loops is controlled by an integrated gene regulatory network consisting of Activin, bone morphogenetic protein (BMP), fibroblast growth factor (FGF), and Follistatin within the incisor stem cell niche. Mesenchymal FGF3 stimulates epithelial stem cell proliferation, and BMP4 represses Fgf3 expression. In turn, Activin, which is strongly expressed in labial mesenchyme, inhibits the repressive effect of BMP4 and restricts Fgf3 expression to labial dental mesenchyme, resulting in increased stem cell proliferation and a large, labial stem cell niche. Follistatin limits the number of lingual stem cells, further contributing to the characteristic asymmetry of mouse incisors, and on the basis of our findings, we suggest a model in which Follistatin antagonizes the activity of Activin. These results show how the spatially restricted and balanced effects of specific components of a signaling network can regulate stem cell proliferation in the niche and account for asymmetric organogenesis. Subtle variations in this or related regulatory networks may explain the different regenerative capacities of various organs and animal species. Public Library of Science 2007-06 2007-06-12 /pmc/articles/PMC1885832/ /pubmed/17564495 http://dx.doi.org/10.1371/journal.pbio.0050159 Text en © 2007 Wang 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
Wang, Xiu-Ping
Suomalainen, Marika
Felszeghy, Szabolcs
Zelarayan, Laura C
Alonso, Maria T
Plikus, Maksim V
Maas, Richard L
Chuong, Cheng-Ming
Schimmang, Thomas
Thesleff, Irma
An Integrated Gene Regulatory Network Controls Stem Cell Proliferation in Teeth
title An Integrated Gene Regulatory Network Controls Stem Cell Proliferation in Teeth
title_full An Integrated Gene Regulatory Network Controls Stem Cell Proliferation in Teeth
title_fullStr An Integrated Gene Regulatory Network Controls Stem Cell Proliferation in Teeth
title_full_unstemmed An Integrated Gene Regulatory Network Controls Stem Cell Proliferation in Teeth
title_short An Integrated Gene Regulatory Network Controls Stem Cell Proliferation in Teeth
title_sort integrated gene regulatory network controls stem cell proliferation in teeth
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1885832/
https://www.ncbi.nlm.nih.gov/pubmed/17564495
http://dx.doi.org/10.1371/journal.pbio.0050159
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