A role of FRK in regulation of embryonal pancreatic beta cell formation.

The fyn-related-kinase (FRK) is a non-receptor tyrosine kinase expressed in various tissues, and among them, is the islets of Langerhans. The role of FRK in pancreatic beta cells has been addressed by studies of knockout or FRK transgenic mice. These experiments have shown that FRK overexpression in beta cells leads to an increased susceptibility to the beta cell toxin streptozotocin and to cytotoxic cytokines, suggesting that FRK may participate in events leading to beta cell destruction. However, these mice also exhibit an increased relative beta cell volume and increased beta cell replication following partial pancreatectomy, suggesting a positive role for FRK in the regulation of beta cell number as well. To further assess the significance of FRK for beta cell replication, we studied the beta cell area and islet cell replication in FRK null mice. We currently observed that the FRK knockout mouse showed no difference in the insulin positive cell area or in the percentage of Ki67-stained proliferating islet cells at adulthood, when compared to wild-type control. In addition, adult FRK(-/-) mice performed normally when subjected to an intravenous glucose tolerance test. To elucidate whether FRK affects pancreatic beta cell number during embryogenesis and shortly after birth, pancreata were collected from FRK(-/-) mice at these stages. Histological analysis of insulin stained pancreatic sections showed that the insulin positive cell area in FRK(-/-) mice was reduced at embryonal day 15 and at birth to 31 and 70% of that of wild-type mice, respectively. FRK(-/-) pancreas weight on day 1 neonatally was similar to that of the control, indicating that the obtained results were not due to altered pancreatic growth. Taken together, these results show that FRK affects beta cell number during embryogenesis and early in life, but is probably redundant for beta cell number and function in adult animals under normal conditions.