Mechanism of Differentiation of Pancreatic β Cells

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To elucidate the molecular mechanism for differentiation of pancreatic β cells, we studied the changes in the expression of various transcription factors during differentiation of pancreatic AR42J cells to insulin-producing cells. These cells are amylase-secreting tumor cells and differentiate to insulin-secreting cells in response to activin A and hepatocyte growth factor (HGF). We studied the changes in the expression of variou transcription factors expressed in pancreatic islets by RT-PCR.Among various transcription factors studied, expression of Pax4 and neurogenin3 (ngn3) was markedly increased during the differentiation. Thus, the expression of Pax4 and ngn3 was not detectable in naive AR42J cells but induced after the treatment with activin A and HGF.It was activin A but not HGF that induced the expression of Pax4 and ngn3. To assess the functional significance of these transcription factors, we introduced cDNA for Pax4 or ngn3 in naive AR42J cells and examined the changes in morphology and expression of various differentiation markers. We also studied the effect of introducing antisense cDNA.When Pax 4 was introduced into naive AR42J cells, nothing happened. Furthermore, introduction of antisense cDNA did not affect the ddiferentiation induced by activin A and HGF.In contrast, transfection of Pax4 to naive AR42J cells induced morphological changes. Thus, cells extended neurite-like processes, Also, expression of pancreatic polypeptide was induced by transfection of ngn3. Additionally, reduction of ngn3 expression resulted in the inhibition of differentation of AR42J into insulin-secreting cells. We conclude that induction of ngn3 expression is critical in differentiation of AR42J cells by activin A.