Neogenesis of beta-cells in adult BETA2/NeuroD-deficient mice.
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 beta-cell neogenesis. Morphometric examination indicates that pancreatic beta-, but not alpha-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 beta-cells of BETA2/NeuroD-deficient mice come from two sources: either directly budding from the pancreatic ductal tree or from the preexisting beta-cells in the residual endocrine pancreas. Our results indicate that beta-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 beta-cell regeneration.
Huang
Hsiang-po
HP
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston Texas 77030, USA.
Chu
Khoi
K
Nemoz-Gaillard
Eric
E
Elberg
Dorit
D
Tsai
Ming-Jer
MJ
D000818:Animals; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D003920:Diabetes Mellitus / Q000235:genetics / Q000401:mortality; D005951:Glucose Tolerance Test; D018257:Helix-Loop-Helix Motifs; D007150:Immunohistochemistry; D007515:Islets of Langerhans / Q000196:embryology / Q000473:pathology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008938:Mitosis; D009024:Morphogenesis; D010183:Pancreatic Ducts / Q000473:pathology; D012038:Regeneration; D015534:Trans-Activators / Q000172:deficiency* / Q000235:genetics / Q000502:physiology
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D015534:Trans-Activators; C501008:Neurod1 protein, mouse