title: Neurogenin3 cooperates with Foxa2 to autoactivate its own expression.
abstract: The transcription factor Neurogenin3 functions as a master regulator of endocrine pancreas formation, and its deficiency leads to the development of diabetes in humans and mice. In the embryonic pancreas, Neurogenin3 is transiently expressed at high levels for a narrow time window to initiate endocrine differentiation in scattered progenitor cells. The mechanisms controlling these rapid and robust changes in Neurogenin3 expression are poorly understood. In this study, we characterize a Neurogenin3 positive autoregulatory loop whereby this factor may rapidly induce its own levels. We show that Neurogenin3 binds to a conserved upstream fragment of its own gene, inducing deposition of active chromatin marks and the activation of Neurog3 transcription. Additionally, we show that the broadly expressed endodermal forkhead factors Foxa1 and Foxa2 can cooperate synergistically to amplify Neurogenin3 autoregulation in vitro. However, only Foxa2 colocalizes with Neurogenin3 in pancreatic progenitors, thus indicating a primary role for this factor in regulating Neurogenin3 expression in vivo. Furthermore, in addition to decreasing Neurog3 autoregulation, inhibition of Foxa2 by RNA interference attenuates Neurogenin3-dependent activation of the endocrine developmental program in cultured duct mPAC cells. Hence, these data uncover the potential functional cooperation between the endocrine lineage-determining factor Neurogenin3 and the widespread endoderm progenitor factor Foxa2 in the implementation of the endocrine developmental program in the pancreas.
authors.affiliation: Diabetes and Obesity Laboratory, Institut D'Investigacions Biomèdiques August Pi i Sunyer-Hospital Clínic, 08036 Barcelona, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Ejarque
authors.forename: Sara
authors.initials: S
authors.lastname: Cervantes
authors.forename: Gemma
authors.initials: G
authors.lastname: Pujadas
authors.forename: Anna
authors.initials: A
authors.lastname: Tutusaus
authors.forename: Lidia
authors.initials: L
authors.lastname: Sanchez
authors.forename: Rosa
authors.initials: R
authors.lastname: Gasa
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000819:agonists / Q000096:biosynthesis* / Q000235:genetics; D002454:Cell Differentiation / Q000502:physiology*; D019070:Cell Lineage / Q000502:physiology; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics / Q000378:metabolism; D051542:Hepatocyte Nuclear Factor 3-beta / Q000819:agonists / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007515:Islets of Langerhans / Q000166:cytology / Q000196:embryology*; D051379:Mice; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000096:biosynthesis* / Q000235:genetics; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002843:Chromatin; D051541:Hepatocyte Nuclear Factor 3-alpha; D051542:Hepatocyte Nuclear Factor 3-beta; D009419:Nerve Tissue Proteins; C496500:Foxa1 protein, mouse; C496503:Foxa2 protein, mouse; C407737:Neurog3 protein, mouse