The homeodomain-containing transcription factors Arx and Pax4 control enteroendocrine subtype specification in mice.

Intestinal hormones are key regulators of digestion and energy homeostasis secreted by rare enteroendocrine cells. These cells produce over ten different hormones including GLP-1 and GIP peptides known to promote insulin secretion. To date, the molecular mechanisms controlling the specification of t...

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Autores principales:	Anthony Beucher, Elisabet Gjernes, Caitlin Collin, Monica Courtney, Aline Meunier, Patrick Collombat, Gérard Gradwohl
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c0837999b685493384adbfd4041922c9
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spelling	oai:doaj.org-article:c0837999b685493384adbfd4041922c92021-11-18T07:19:48ZThe homeodomain-containing transcription factors Arx and Pax4 control enteroendocrine subtype specification in mice.1932-620310.1371/journal.pone.0036449https://doaj.org/article/c0837999b685493384adbfd4041922c92012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22570716/?tool=EBIhttps://doaj.org/toc/1932-6203Intestinal hormones are key regulators of digestion and energy homeostasis secreted by rare enteroendocrine cells. These cells produce over ten different hormones including GLP-1 and GIP peptides known to promote insulin secretion. To date, the molecular mechanisms controlling the specification of the various enteroendocrine subtypes from multipotent Neurog3(+) endocrine progenitor cells, as well as their number, remain largely unknown. In contrast, in the embryonic pancreas, the opposite activities of Arx and Pax4 homeodomain transcription factors promote islet progenitor cells towards the different endocrine cell fates. In this study, we thus investigated the role of Arx and Pax4 in enteroendocrine subtype specification. The small intestine and colon of Arx- and Pax4-deficient mice were analyzed using histological, molecular, and lineage tracing approaches. We show that Arx is expressed in endocrine progenitors (Neurog3(+)) and in early differentiating (ChromograninA(-)) GLP-1-, GIP-, CCK-, Sct- Gastrin- and Ghrelin-producing cells. We noted a dramatic reduction or a complete loss of all these enteroendocrine cell types in Arx mutants. Serotonin- and Somatostatin-secreting cells do not express Arx and, accordingly, the differentiation of Serotonin cells was not affected in Arx mutants. However, the number of Somatostatin-expressing D-cells is increased as Arx-deficient progenitor cells are redirected to the D-cell lineage. In Pax4-deficient mice, the differentiation of Serotonin and Somatostatin cells is impaired, as well as of GIP and Gastrin cells. In contrast, the number of GLP-1 producing L-cells is increased concomitantly with an upregulation of Arx. Thus, while Arx and Pax4 are necessary for the development of L- and D-cells respectively, they conversely restrict D- and L-cells fates suggesting antagonistic functions in D/L cell allocation. In conclusion, these finding demonstrate that, downstream of Neurog3, the specification of a subset of enteroendocrine subtypes relies on both Arx and Pax4, while others depend only on Arx or Pax4.Anthony BeucherElisabet GjernesCaitlin CollinMonica CourtneyAline MeunierPatrick CollombatGérard GradwohlPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 5, p e36449 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Anthony Beucher Elisabet Gjernes Caitlin Collin Monica Courtney Aline Meunier Patrick Collombat Gérard Gradwohl The homeodomain-containing transcription factors Arx and Pax4 control enteroendocrine subtype specification in mice.
description	Intestinal hormones are key regulators of digestion and energy homeostasis secreted by rare enteroendocrine cells. These cells produce over ten different hormones including GLP-1 and GIP peptides known to promote insulin secretion. To date, the molecular mechanisms controlling the specification of the various enteroendocrine subtypes from multipotent Neurog3(+) endocrine progenitor cells, as well as their number, remain largely unknown. In contrast, in the embryonic pancreas, the opposite activities of Arx and Pax4 homeodomain transcription factors promote islet progenitor cells towards the different endocrine cell fates. In this study, we thus investigated the role of Arx and Pax4 in enteroendocrine subtype specification. The small intestine and colon of Arx- and Pax4-deficient mice were analyzed using histological, molecular, and lineage tracing approaches. We show that Arx is expressed in endocrine progenitors (Neurog3(+)) and in early differentiating (ChromograninA(-)) GLP-1-, GIP-, CCK-, Sct- Gastrin- and Ghrelin-producing cells. We noted a dramatic reduction or a complete loss of all these enteroendocrine cell types in Arx mutants. Serotonin- and Somatostatin-secreting cells do not express Arx and, accordingly, the differentiation of Serotonin cells was not affected in Arx mutants. However, the number of Somatostatin-expressing D-cells is increased as Arx-deficient progenitor cells are redirected to the D-cell lineage. In Pax4-deficient mice, the differentiation of Serotonin and Somatostatin cells is impaired, as well as of GIP and Gastrin cells. In contrast, the number of GLP-1 producing L-cells is increased concomitantly with an upregulation of Arx. Thus, while Arx and Pax4 are necessary for the development of L- and D-cells respectively, they conversely restrict D- and L-cells fates suggesting antagonistic functions in D/L cell allocation. In conclusion, these finding demonstrate that, downstream of Neurog3, the specification of a subset of enteroendocrine subtypes relies on both Arx and Pax4, while others depend only on Arx or Pax4.
format	article
author	Anthony Beucher Elisabet Gjernes Caitlin Collin Monica Courtney Aline Meunier Patrick Collombat Gérard Gradwohl
author_facet	Anthony Beucher Elisabet Gjernes Caitlin Collin Monica Courtney Aline Meunier Patrick Collombat Gérard Gradwohl
author_sort	Anthony Beucher
title	The homeodomain-containing transcription factors Arx and Pax4 control enteroendocrine subtype specification in mice.
title_short	The homeodomain-containing transcription factors Arx and Pax4 control enteroendocrine subtype specification in mice.
title_full	The homeodomain-containing transcription factors Arx and Pax4 control enteroendocrine subtype specification in mice.
title_fullStr	The homeodomain-containing transcription factors Arx and Pax4 control enteroendocrine subtype specification in mice.
title_full_unstemmed	The homeodomain-containing transcription factors Arx and Pax4 control enteroendocrine subtype specification in mice.
title_sort	homeodomain-containing transcription factors arx and pax4 control enteroendocrine subtype specification in mice.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/c0837999b685493384adbfd4041922c9
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The homeodomain-containing transcription factors Arx and Pax4 control enteroendocrine subtype specification in mice.

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