Journal Article

β-Cell Proliferation, but Not Neogenesis, Following 60% Partial Pancreatectomy Is Impaired in the Absence of FoxM1

Amanda Ackermann Misfeldt, Maureen Gannon, Robert H. Costa

2008

Overview

β-Cell Proliferation, but Not Neogenesis, Following 60% Partial Pancreatectomy Is Impaired in the Absence of FoxM1 Amanda Ackermann Misfeldt 1 2 , Robert H. Costa 3 and Maureen Gannon 1 2 4 5 1 Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 2 Program in Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee 3 Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois 4 Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, Tennessee 5 Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee Corresponding author: Maureen Gannon, maureen.gannon{at}vanderbilt.edu Abstract OBJECTIVE— This study was designed to determine whether the transcription factor FoxM1 was required for regeneration of β-cell mass via proliferation and/or neogenesis in the adult after 60% partial pancreatectomy (PPx). RESEARCH DESIGN AND METHODS— Adult mice with a pancreas-wide deletion of Foxm1 ( Foxm1 flox/flox ; Pdx1-Cre [FoxM1 Δpanc ]) and their control littermates ( Foxm1 flox/flox ) were subjected to PPx or a sham operation, after which islet expression of Foxm1 and several target genes, β-cell mass, proliferation, β-cell size, islet size, islet density, and neurogenin-3 expression were analyzed. RESULTS— In control mice, PPx stimulated β-cell proliferation and neogenesis and upregulated Foxm1 and several of its known targets ( Plk1 , Cenp-a , Birc5/Survivin , and Ccnb1 ) in islets. Within 1 week post-PPx, control mice underwent significant regeneration of β-cell mass, and average islet size within the regenerating lobe was similar to that after a sham operation. However, FoxM1 Δpanc mice exhibited specific impairments in β-cell mass regeneration and islet growth after PPx, with reduced proliferation of α- and β-cells but no impairments in acinar or ductal cell proliferation. Interestingly, FoxM1 was not required for proliferation of β-cells within small endocrine cell clusters located in the regenerating portion of the pancreas but was specifically required for proliferation of β-cells within larger islets. Additionally, FoxM1 was not required for β-cell neogenesis following PPx. CONCLUSIONS— Our results indicate that FoxM1 is partially required for increased β-cell proliferation, but not β-cell neogenesis, stimulated by PPx. Furthermore, FoxM1 seems to be dispensable for proliferation of β-cells following neogenesis but is required for proliferation of preexisting β-cells. Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 26 August 2008. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. 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 August 15, 2008. Received July 1, 2008. DIABETES

• Publisher: American Diabetes Association
• Subject: Animals / Biological and medical sciences / Cell Nucleus Size / Cell Proliferation / Diabetes. Impaired glucose tolerance / DNA binding proteins / Endocrine pancreas. Apud cells (diseases) / Endocrinopathies / Etiopathogenesis. Screening. Investigations. Target tissue resistance / Forkhead Box Protein M1 / Forkhead Transcription Factors - genetics / Forkhead Transcription Factors - physiology / Health aspects / Insulin-Secreting Cells - cytology / Insulin-Secreting Cells - metabolism / Islet Studies / Islets of Langerhans - cytology / Islets of Langerhans - metabolism / Medical sciences / Mice / Mice, Inbred C57BL / Mice, Inbred Strains / Mice, Knockout / Pancreatectomy / Pancreatectomy - adverse effects / Pancreatectomy - methods / Pancreatic beta cells / Patient outcomes / Physiological aspects