Neonatal β cell development in mice and humans is regulated by calcineurin/NFAT.
Little is known about the mechanisms governing neonatal growth and maturation of organs. Here we demonstrate that calcineurin/Nuclear Factor of Activated T cells (Cn/NFAT) signaling regulates neonatal pancreatic development in mouse and human islets. Inactivation of calcineurin b1 (Cnb1) in mouse islets impaired dense core granule biogenesis, decreased insulin secretion, and reduced cell proliferation and mass, culminating in lethal diabetes. Pancreatic β cells lacking Cnb1 failed to express genes revealed to be direct NFAT targets required for replication, insulin storage, and secretion. In contrast, glucokinase activation stimulated Cn-dependent expression of these genes. Calcineurin inhibitors, such as tacrolimus, used for human immunosuppression, induce diabetes. Tacrolimus exposure reduced Cn/NFAT-dependent expression of factors essential for insulin dense core granule formation and secretion and neonatal β cell proliferation, consistent with our genetic studies. Discovery of conserved pathways regulating β cell maturation and proliferation suggests new strategies for controlling β cell growth or replacement in human islet diseases.
Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
William R
WR
Goodyer
Xueying
X
Gu
Yinghua
Y
Liu
Rita
R
Bottino
Gerald R
GR
Crabtree
Seung K
SK
Kim
D000328:Adult; D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000502:physiology; D019703:Calcineurin / Q000235:genetics* / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D050778:NFATC Transcription Factors / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology; D055815:Young Adult
D051792:Basic Helix-Loop-Helix Proteins; D019703:Calcineurin; D050778:NFATC Transcription Factors; D009419:Nerve Tissue Proteins; C494003:NFATC1 protein, human; C407737:Neurog3 protein, mouse; C525676:PPP3R1 protein, human