The homeodomain-containing transcription factors Arx and Pax4 control enteroendocrine subtype specification in mice. - Archive ouverte HAL Access content directly
Journal Articles PLoS ONE Year : 2012

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

Anthony Beucher
  • Function : Author
Elisabet Gjernes
  • Function : Author
Caitlin Collin
  • Function : Author
Monica Courtney
  • Function : Author
Aline Meunier

Abstract

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.

Dates and versions

hal-00760293 , version 1 (03-12-2012)

Identifiers

Cite

Anthony Beucher, Elisabet Gjernes, Caitlin Collin, Monica Courtney, Aline Meunier, et al.. The homeodomain-containing transcription factors Arx and Pax4 control enteroendocrine subtype specification in mice.. PLoS ONE, 2012, 7 (5), pp.e36449. ⟨10.1371/journal.pone.0036449⟩. ⟨hal-00760293⟩
180 View
0 Download

Altmetric

Share

Gmail Facebook X LinkedIn More