OVO homologue-like 1 (Ovol1) transcription factor: a novel target of neurogenin-3 in rodent pancreas

• Published in: Diabetologia Vol. 53; no. 1; pp. 115 - 122
• Main Authors: Vetere, A, Li, W.-C, Paroni, F, Juhl, K, Guo, L, Nishimura, W, Dai, X, Bonner-Weir, S, Sharma, A
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Berlin/Heidelberg : Springer-Verlag 01.01.2010; Springer-Verlag; Springer; Springer Nature B.V
• Subjects: Animals; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biological and medical sciences; Cell Differentiation; Cell Division; Cell Line; Cell Proliferation; Cloning; Cloning, Molecular; Diabetes; Diabetes. Impaired glucose tolerance; DNA Primers - genetics; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Exons; Gene expression; Gene Expression Regulation; Human Physiology; Internal Medicine; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins - metabolism; Pancreas; Pancreas - cytology; Pancreas - pathology; Pancreatectomy; Plasmids; Proteins; Rats; Rats, Sprague-Dawley; Regeneration; Reverse Transcriptase Polymerase Chain Reaction; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; United States > US; Pancreatic progenitors; ChIP cloning; Proliferation/differentiation; Neurogenin 3; Endocrinopathy; Cell proliferation; Diabetes mellitus; Rodentia; Vertebrata; Mammalia; Differentiation; Transcription factor; Pancreas
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-009-1567-5

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.