AIMS/HYPOTHESIS: The basic helix-loop-helix transcription factor neurogenin-3 (NGN3) commits the fates of pancreatic progenitors to endocrine cell types, but knowledge of the mechanisms regulating the choice between proliferation and differentiation of these progenitors is limited. METHODS: Using a chromatin immunoprecipitation cloning approach, we searched for direct targets of NGN3 and identified a zinc-finger transcription factor, OVO homologue-like 1 (OVOL1). Transactivation experiments were carried out to elucidate the functional role of NGN3 in Ovol1 gene expression. Embryonic and adult rodents pancreases were immunostained for OVOL1, Ki67 and NGN3. RESULTS: We showed that NGN3 negatively regulates transcription of Ovol1 in an E-box-dependent fashion. The presence of either NGN3 or NEUROD1, but not MYOD, reduced endogenous Ovol1 mRNA. OVOL1 was detected in pancreatic tissue around embryonic day 15.5, after which OVOL1 levels dramatically increased. In embryonic pancreas, OVOL1 protein levels were low in NGN3(+) or Ki67(+) cells, but high in quiescent differentiated cells. OVOL1 presence was maintained in adult pancreas, where it was detected in islets, pancreatic ducts and some acinar cells. Additionally OVOL1 presence was lacking in proliferating ductules in regenerating pancreas and induced in cells as they began to acquire their differentiated phenotype. CONCLUSIONS/ INTERPRETATION: The timing of OVOL1 appearance in pancreas and its increased levels in differentiated cells suggest that OVOL1 promotes the transition of cells from a proliferating, less-differentiated state to a quiescent more-differentiated state. We conclude that OVOL1, a downstream target of NGN3, may play an important role in regulating the balance between proliferation and differentiation of pancreatic cells.
AIMS/HYPOTHESIS: The basic helix-loop-helix transcription factor neurogenin-3 (NGN3) commits the fates of pancreatic progenitors to endocrine cell types, but knowledge of the mechanisms regulating the choice between proliferation and differentiation of these progenitors is limited. METHODS: Using a chromatin immunoprecipitation cloning approach, we searched for direct targets of NGN3 and identified a zinc-finger transcription factor, OVO homologue-like 1 (OVOL1). Transactivation experiments were carried out to elucidate the functional role of NGN3 in Ovol1 gene expression. Embryonic and adult rodents pancreases were immunostained for OVOL1, Ki67 and NGN3. RESULTS: We showed that NGN3 negatively regulates transcription of Ovol1 in an E-box-dependent fashion. The presence of either NGN3 or NEUROD1, but not MYOD, reduced endogenous Ovol1 mRNA. OVOL1 was detected in pancreatic tissue around embryonic day 15.5, after which OVOL1 levels dramatically increased. In embryonic pancreas, OVOL1 protein levels were low in NGN3(+) or Ki67(+) cells, but high in quiescent differentiated cells. OVOL1 presence was maintained in adult pancreas, where it was detected in islets, pancreatic ducts and some acinar cells. Additionally OVOL1 presence was lacking in proliferating ductules in regenerating pancreas and induced in cells as they began to acquire their differentiated phenotype. CONCLUSIONS/ INTERPRETATION: The timing of OVOL1 appearance in pancreas and its increased levels in differentiated cells suggest that OVOL1 promotes the transition of cells from a proliferating, less-differentiated state to a quiescent more-differentiated state. We conclude that OVOL1, a downstream target of NGN3, may play an important role in regulating the balance between proliferation and differentiation of pancreatic cells.
Authors: Baoan Li; Mahalakshmi Nair; Douglas R Mackay; Virginia Bilanchone; Ming Hu; Magid Fallahi; Hanqiu Song; Qian Dai; Paula E Cohen; Xing Dai Journal: Development Date: 2005-02-16 Impact factor: 6.868
Authors: Andreas Petri; Jonas Ahnfelt-Rønne; Klaus Stensgaard Frederiksen; David George Edwards; Dennis Madsen; Palle Serup; Jan Fleckner; R Scott Heller Journal: J Mol Endocrinol Date: 2006-10 Impact factor: 5.098
Authors: A Apelqvist; H Li; L Sommer; P Beatus; D J Anderson; T Honjo; M Hrabe de Angelis; U Lendahl; H Edlund Journal: Nature Date: 1999-08-26 Impact factor: 49.962
Authors: A Sharma; D H Zangen; P Reitz; M Taneja; M E Lissauer; C P Miller; G C Weir; J F Habener; S Bonner-Weir Journal: Diabetes Date: 1999-03 Impact factor: 9.461
Authors: Georg Mellitzer; Stefan Bonné; Reini F Luco; Mark Van De Casteele; Nathalie Lenne-Samuel; Patrick Collombat; Ahmed Mansouri; Jacqueline Lee; Michael Lan; Daniel Pipeleers; Finn C Nielsen; Jorge Ferrer; Gérard Gradwohl; Harry Heimberg Journal: EMBO J Date: 2006-03-02 Impact factor: 11.598