Novel Function of the Ciliogenic Transcription Factor RFX3 in Development of the Endocrine Pancreas

• Published in: Diabetes (New York, N.Y.) Vol. 56; no. 4; pp. 950 - 959
• Main Authors: AIT-LOUNIS, Aouatef, BAAS, Dominique, BARRAS, Emmanuèle, BENADIBA, Carine, CHAROLLAIS, Anne, NLEND, Rachel Nlend, LIEGEOIS, Delphine, MEDA, Paolo, DURAND, Bénédicte, REITH, Walter
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.04.2007
• Subjects: Animals; Antibodies; Biological and medical sciences; Cilia; Cilia - physiology; Cilia - ultrastructure; Crosses, Genetic; Defects; Diabetes; Diabetes mellitus; Diabetes. Impaired glucose tolerance; DNA binding; DNA-Binding Proteins; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; DNA-ligand interactions; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Genetic aspects; Genetic regulation; Genetics; Ghrelin; Glucagon; Glucose Tolerance Test; Insulin; Islets of Langerhans; Islets of Langerhans - cytology; Islets of Langerhans - physiology; Life Sciences; Medical sciences; Mice; Mice, Knockout; Mutation; Pancreas; Peptide Hormones; Peptide Hormones - analysis; Pregnancy; Proteins; Regulatory Factor X Transcription Factors; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Messenger - genetics; Signal transduction; Stem Cells; Stem Cells - cytology; Stem Cells - physiology; TATA-Box Binding Protein; TATA-Box Binding Protein - genetics; Transcription Factors; Transcription Factors - deficiency; Transcription Factors - genetics; Transcription Factors - physiology; Endocrinopathy; Development; Transcription factor; Diabetes mellitus; Endocrine pancreas
• DOI: 10.2337/db06-1187
• ISSN: 0012-1797

Novel Function of the Ciliogenic Transcription Factor RFX3 in Development of the Endocrine Pancreas Aouatef Ait-Lounis 1 , Dominique Baas 2 3 , Emmanuèle Barras 1 , Carine Benadiba 2 , Anne Charollais 4 , Rachel Nlend Nlend 4 , Delphine Liègeois 4 , Paolo Meda 4 , Bénédicte Durand 2 and Walter Reith 1 1 Department of Pathology and Immunology, University of Geneva Medical School, Geneva, Switzerland 2 Centre de Génétique Moléculaire et Cellulaire, Université Claude Bernard, Villeurbanne, France 3 Equipe Différenciation Neuromusculaire, Lyon, France 4 Department of Cell Physiology and Metabolism, University of Geneva Medical School, Geneva, Switzerland Address correspondence and reprint requests to Walter Reith, Department of Pathology and Immunology, University of Geneva Medical School, 1 Rue Michel-Servet, CH-1211, Geneva, Switzerland. E-mail: walter.reith{at}medecine.unige.ch Abstract The transcription factor regulatory factor X (RFX)-3 regulates the expression of genes required for the growth and function of cilia. We show here that mouse RFX3 is expressed in developing and mature pancreatic endocrine cells during embryogenesis and in adults. RFX3 expression already is evident in early Ngn3-positive progenitors and is maintained in all major pancreatic endocrine cell lineages throughout their development. Primary cilia of hitherto unknown function present on these cells consequently are reduced in number and severely stunted in Rfx3 −/− mice. This ciliary abnormality is associated with a developmental defect leading to a uniquely altered cellular composition of the islets of Langerhans. Just before birth, Rfx3 −/− islets contain considerably less insulin-, glucagon-, and ghrelin-producing cells, whereas pancreatic polypeptide–positive cells are markedly increased in number. In adult mice, the defect leads to small and disorganized islets, reduced insulin production, and impaired glucose tolerance. These findings suggest that RFX3 participates in the mechanisms that govern pancreatic endocrine cell differentiation and that the presence of primary cilia on islet cells may play a key role in this process. dpc, day postcoitum Hh, hedgehog IFT, intraflagellar transport PP, pancreatic polypeptide RFX, regulatory factor X Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 17 January 2007. DOI: 10.2337/db06-1187. Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db06-1187 . The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted January 5, 2007. Received August 25, 2006. DIABETES