title: The homeodomain-containing transcription factors Arx and Pax4 control enteroendocrine subtype specification in mice.
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.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM) U964, Centre National de Recherche Scientifique (CNRS) UMR 7104, Université de Strasbourg, Illkirch, France.
authors.forename: Anthony
authors.initials: A
authors.lastname: Beucher
authors.forename: Elisabet
authors.initials: E
authors.lastname: Gjernes
authors.forename: Caitlin
authors.initials: C
authors.lastname: Collin
authors.forename: Monica
authors.initials: M
authors.lastname: Courtney
authors.forename: Aline
authors.initials: A
authors.lastname: Meunier
authors.forename: Patrick
authors.initials: P
authors.lastname: Collombat
authors.forename: Gérard
authors.initials: G
authors.lastname: Gradwohl
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D019858:Enteroendocrine Cells / Q000145:classification / Q000166:cytology / Q000378:metabolism*; D015870:Gene Expression; D005786:Gene Expression Regulation; D052216:Glucagon-Like Peptide 1 / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D008954:Models, Biological; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D051761:Paired Box Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D036361:Peptide Hormones / Q000235:genetics; D013004:Somatostatin / Q000235:genetics; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D052216:Glucagon-Like Peptide 1; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D051761:Paired Box Transcription Factors; D036361:Peptide Hormones; D013004:Somatostatin; D014157:Transcription Factors; C469265:ARX protein, mouse; C407737:Neurog3 protein, mouse; C110218:Pax4 protein, mouse