PERK EIF2AK3 control of pancreatic beta cell differentiation and proliferation is required for postnatal glucose homeostasis.
Mutations in PERK (EIF2AK3) result in permanent neonatal diabetes as well as several other anomalies that underlie the human Wolcott-Rallison syndrome, and these anomalies are mirrored in Perk knockout mice. To identify the cause of diabetes in PERK-deficient mice, we generated a series of tissue- and cell-specific knockouts of the Perk gene and performed a developmental analysis of the progression to overt diabetes. We discovered that PERK is specifically required in the insulin-secreting beta cells during the fetal and early neonatal period as a prerequisite for postnatal glucose homeostasis. However, PERK expression in beta cells is not required at the adult stage to maintain beta cell functions and glucose homeostasis. We show that PERK-deficient mice exhibit severe defects in fetal/neonatal beta cell proliferation and differentiation, resulting in low beta cell mass, defects in proinsulin trafficking, and abrogation of insulin secretion that culminate in permanent neonatal diabetes.
Zhang
Wei
W
Department of Biology, Pennsylvania State University, University Park, Pennsylvania 16802, USA.
Feng
Daorong
D
Li
Yulin
Y
Iida
Kaori
K
McGrath
Barbara
B
Cavener
Douglas R
DR
D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D003920:Diabetes Mellitus / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D005333:Fetus / Q000201:enzymology / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D005947:Glucose / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007231:Infant, Newborn; D050417:Insulin-Secreting Cells / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011384:Proinsulin / Q000235:genetics / Q000378:metabolism; D019892:eIF-2 Kinase / Q000172:deficiency / Q000378:metabolism*
D005947:Glucose; D011384:Proinsulin; D019892:eIF-2 Kinase