Abstract
Aims/hypothesisPw1 or paternally-expressed gene 3 (Peg3) encodes a zinc finger transcription factor that is widely expressed during mouse embryonic development and later restricted to multiple somatic stem cell lineages in the adult. The aim of the present study was to define Pw1 expression in the embryonic and adult pancreas and investigate its role in the beta cell cycle in Pw1 wild-type and mutant mice.MethodsWe analysed PW1 expression by immunohistochemistry in pancreas of nonpregant and pregnant mice and following injury by partial duct ligation. Its role in the beta cell cycle was studied in vivo using a novel conditional knockout mouse and in vitro by lentivirus-mediated gene knockdown.ResultsWe showed that PW1 is expressed in early pancreatic progenitors at E9.5 but becomes progressively restricted to fully differentiated beta cells as they become established after birth and withdraw from the cell cycle. Notably, PW1 expression declines when beta cells are induced to proliferate and loss of PW1 function activates the beta cell cycle.Conclusions/interpretationThese results indicate that PW1 is a co-regulator of the beta cell cycle and can thus be considered a novel therapeutic target in diabetes.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-016-3954-z) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Highlights
Under physiological conditions, beta cell division declines continuously after birth in both humans and rodents [1]
PW1 restrains the beta cell cycle As PW1 is involved in growth arrest in several cell types, we investigated its presence in cycling beta cells
Since pancreatic and duodenal homeobox 1 (PDX1) is necessary for pancreas specification and essential for adult beta cells [27] and since PW1 controls the cycling of other cell types [10, 28], we investigated whether PW1 affects beta cell cycling in the embryonic and postnatal pancreas
Summary
Beta cell division declines continuously after birth in both humans and rodents [1]. In vitro studies have shown that PW1 mediates p53–Bax signalling in the p53 growth arrest and cell death pathway activated by DNA damage, possibly by interacting with Siah to induce Bax translocation to the mitochondria [8,9,10]. Consistent with these in vitro studies, loss of Pw1 expression correlates with increased cell proliferation and tumour grade in gynaecological and glioma cell lines [6, 7, 11]. The ‘pan-stem cell’ pattern of Pw1 expression in the adult prompted us to examine its expression in the pancreas during embryonic development and adulthood
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