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Neogenesis of ß-Cells in Adult BETA2/NeuroD-Deficient Mice

Department of Molecular and Cellular Biology (H.-p.H., K.C., E.N.-G., D.E., M.-J.T.), Medicine (M.-J.T.) and Program in Developmental Biology (M.-J.T.), Baylor College of Medicine, Houston Texas 77030

Address all correspondence and requests for reprints to: Ming-Jer Tsai, Ph.D., Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030. E-mail: mtsai{at}bcm.tmc.edu.

BETA2/NeuroD, a basic helix-loop-helix transcription factor, is expressed in pancreatic endocrine cells during development and regulates insulin gene expression. We demonstrated previously that the endocrine pancreas of BETA2/NeuroD-deficient mice undergoes massive apoptosis and, consequently, animals die of diabetes shortly after birth. Here we show that a significant fraction of BETA2-deficient mice in a new genetic background can survive diabetes and live to adulthood through the process of ß-cell neogenesis. Morphometric examination indicates that pancreatic ß-, but not -cell mass, was restored to a level comparable to that of wild-type animals. However, the newly formed islet cells cannot form mature islets of Langerhans, indicating an indispensable role of BETA2 in morphogenesis of normal islet structure. Furthermore, immunohistochemical examinations revealed that newly formed ß-cells of BETA2/NeuroD-deficient mice come from two sources: either directly budding from the pancreatic ductal tree or from the preexisting ß-cells in the residual endocrine pancreas. Our results indicate that ß-cell neogenesis in our BETA2/NeuroD-deficient mice contributes to their survival, and these mice may provide a useful model for studying the mechanism of ß-cell regeneration.

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