title: Arx is required for normal enteroendocrine cell development in mice and humans.
abstract: Enteroendocrine cells of the gastrointestinal (GI) tract play a central role in metabolism, digestion, satiety and lipid absorption, yet their development remains poorly understood. Here we show that Arx, a homeodomain-containing transcription factor, is required for the normal development of mouse and human enteroendocrine cells. Arx expression is detected in a subset of Neurogenin3 (Ngn3)-positive endocrine progenitors and is also found in a subset of hormone-producing cells. In mice, removal of Arx from the developing endoderm results in a decrease of enteroendocrine cell types including gastrin-, glucagon/GLP-1-, CCK-, secretin-producing cell populations and an increase of somatostatin-expressing cells. This phenotype is also observed in mice with endocrine-progenitor-specific Arx ablation suggesting that Arx is required in the progenitor for enteroendocrine cell development. In addition, depletion of human ARX in developing human intestinal tissue results in a profound deficit in expression of the enteroendocrine cell markers CCK, secretin and glucagon while expression of a pan-intestinal epithelial marker, CDX2, and other non-endocrine markers remained unchanged. Taken together, our findings uncover a novel and conserved role of Arx in mammalian endocrine cell development and provide a potential cause for the chronic diarrhea seen in both humans and mice carrying Arx mutations.
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, USA.
authors.forename: Aiping
authors.initials: A
authors.lastname: Du
authors.forename: Kyle W
authors.initials: KW
authors.lastname: McCracken
authors.forename: Erik R
authors.initials: ER
authors.lastname: Walp
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Terry
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Klein
authors.forename: Annie
authors.initials: A
authors.lastname: Han
authors.forename: James M
authors.initials: JM
authors.lastname: Wells
authors.forename: Catherine Lee
authors.initials: CL
authors.lastname: May
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D004707:Endoderm / Q000166:cytology / Q000196:embryology*; D019858:Enteroendocrine Cells / Q000166:cytology*; D018398:Homeodomain Proteins / Q000502:physiology*; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; C469264:ARX protein, human; C469265:ARX protein, mouse; C498695:NEUROG3 protein, human; C407737:Neurog3 protein, mouse