Retinoblastoma tumor suppressor protein in pancreatic progenitors controls α- and β-cell fate

• Published in: Proceedings of the National Academy of Sciences - PNAS 2013-09, Vol.110 (36), p.14723-14728
• Main Authors: Cai, Erica P., Wu, Xiaohong, Schroer, Stephanie A., Elia, Andrew J., Nostro, M. Cristina, Zacksenhaus, Eldad, Woo, Minna
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Base Sequence; Beta cells; Biological Sciences; Cell cycle; Cell Differentiation - genetics; Cell Line, Tumor; Cell lines; Cell Survival - genetics; Cellular differentiation; Developmental biology; Diabetes; Diabetes Mellitus, Experimental - genetics; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - pathology; E2F1 Transcription Factor - genetics; E2F1 Transcription Factor - metabolism; Female; Gene expression regulation; Glucagon-Secreting Cells - cytology; Glucagon-Secreting Cells - metabolism; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Immunohistochemistry; Insulin; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - metabolism; Islet cells; Islets of Langerhans - cytology; Islets of Langerhans - metabolism; Male; Mice; Mice, Knockout; Mice, Transgenic; Progenitor cells; Retinoblastoma Protein - genetics; Retinoblastoma Protein - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Sequence Homology, Nucleic Acid; Stem Cells - cytology; Stem Cells - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1303386110

Pancreatic endocrine cells expand rapidly during embryogenesis by neogenesis and proliferation, but during adulthood, islet cells have a very slow turnover. Disruption of murine retinoblastoma tumor suppressor protein (Rb) in mature pancreatic β-cells has a limited effect on cell proliferation. Here we show that deletion of Rb during embryogenesis in islet progenitors leads to an increase in the neurogenin 3-expressing precursor cell population, which persists in the postnatal period and is associated with increased β-cell mass in adults. In contrast, Rb-deficient islet precursors, through repression of the cell fate factor aristaless related homeobox, result in decreased α-cell mass. The opposing effect on survival of Rb-deficient α- and β-cells was a result of opposing effects on p53 in these cell types. As a consequence, loss of Rb in islet precursors led to a reduced α- to β-cell ratio, leading to improved glucose homeostasis and protection against diabetes.