Insulin-producing pancreatic islet beta cells are destroyed, severely depleted or functionally impaired in diabetes. Therefore, replacing functional beta cell mass would advance clinical diabetes management. We have previously demonstrated the importance of Cdk4 in regulating beta cell mass. Cdk4-deficient mice display beta cell hypoplasia and develop diabetes, whereas beta cell hyperplasia is observed in mice expressing an active Cdk4R24C kinase. While beta cell replication appears to be the primary mechanism responsible for beta cell mass increase, considerable evidence also supports a contribution from the pancreatic ductal epithelium in generation of new beta cells. We conclude that Cdk4 not only promotes beta cell replication, but also facilitates the activation of beta cell progenitors in the ductal epithelium. In addition, we show that Cdk4 controls beta cell mass by recruiting quiescent cells to enter the cell cycle. We show that Cdk4 and its downstream transcription factor E2F1 regulate pancreas development prior to and during the secondary transition. Deficiency of Cdk4 results in reduced embryonic pancreas size due to impaired mesenchyme development and limitation of the number of Pdx1+ pancreatic progenitor cells. Interestingly, expression of activated Cdk4R24C kinase leads to increased Nkx2.2+ and Nkx6.1+ cells and a rise in the number and proliferation of Ngn3+ endocrine precursor cells resulting in expansion of the cell lineage. Further, we show that E2F1 binds and activates the Ngn3 promoter thereby modulating Ngn3 expression levels in the embryonic pancreas in a Cdk4-dependent manner. These results identify Cdk4 as an important regulator of early pancreas development by virtue of its ability to modulate the proliferation potential of pancreatic progenitors and endocrine precursors. We have begun a systematic analyses of other cell cycle regulators in pancreas development and function. We have recently uncovered an important role for CDK2 in beta cell function and post-natal beta cell proliferation. Cdk2 loss results in loss of beta cell function. Further, age associated reduction in beta cell mass is seen upon Cdk2 deficiency. Also, we observe that metabolic stress further accentuates the defecst due to loss of Cdk2 by further deterioration of beta cell mass and function. We are presently investigating the mechanisms that underlie these findings.
