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Connective Tissue Growth Factor (CTGF) Inactivation Leads to Defects in Islet Cell Lineage Allocation and β-Cell Proliferation during Embryogenesis

Departments of Medicine (Y.A.O., M.G.), Division of Diabetes, Endocrinology, and Metabolism and Molecular Physiology and Biophysics (L.A.C., M.A.G., M.G.), Vanderbilt University Medical Center, Nashville, Tennessee 37232; Department of Orthopaedic Surgery (R.A.D., K.M.L., A.E.), David Geffen School of Medicine at UCLA, University of California, Los Angeles, California 90095; Center for Cell and Vascular Biology (D.R.B.), Children’s Research Institute, The Ohio State University, Columbus, Ohio 43205; and Regeneron Pharmaceuticals, Inc. (D.M.V., A.J.M., G.D.Y., A.E.), Tarrytown, New York 10591

Address all correspondence and requests for reprints to: Maureen Gannon, Ph.D., Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, 2213 Garland Avenue, 7425C MRBIV, Nashville, Tennessee 37232-0475. E-mail: maureen.gannon{at}vanderbilt.edu.

The factors necessary for normal pancreatic islet morphogenesis have not been well characterized. Here we report that connective tissue growth factor (CTGF) is involved in the establishment of normal islet endocrine cell ratio and architecture. CTGF is a secreted protein known to modulate several growth factor-signaling pathways including TGF-β, BMP, and Wnt. Although its role in pancreatic diseases such as pancreatitis and pancreatic cancer are well documented, a role for CTGF in normal pancreas development and function has heretofore not been examined. Using a lacZ-tagged CTGF allele, we describe for the first time the expression pattern of CTGF in the developing pancreas and the requirement of CTGF for normal islet morphogenesis and embryonic β-cell proliferation. CTGF is highly expressed in pancreatic ductal epithelium and vascular endothelium, as well as at lower levels in developing insulin⁺ cells, but becomes down-regulated in β-cells soon after birth. Pancreata from CTGF null embryos have an increase in glucagon⁺ cells with a concomitant decrease in insulin⁺ cells, and show defects in islet morphogenesis. Loss of CTGF also results in a dramatic decrease in β-cell proliferation at late gestation. Unlike CTGF null embryos, CTGF heterozygotes survive past birth and exhibit a range of islet phenotypes, including an intermingling of islet cell types, increased number of glucagon⁺ cells, and β-cell hypertrophy.